具有细胞色素P450 3A药酶抑制作用的口服自微乳化给药系统的构建及机制研究
|
摘要
药物的口服吸收是一个复杂的过程,其包括生理因素和制剂因素(如溶解度、组织渗透性、剂型等)。然而,对于那些在体内易被细胞色素P450 3A(CYP 3A)所氧化代谢的药物,抑制CYP 3A的生物转化活性,是提高这类药物口服生物利用度的有效途径。CYP 3A在肝脏及肠道中含量丰富,在成人肝脏和小肠中分别占CYP总量的30%和70%以上,它参与50%以上药物的Ⅰ相代谢,明显降低了CYP 3A底物药物口服生物利用度。
有文献报道,易被CYP 3A酶代谢的药物与CYP 3A抑制剂共同服用,这些药物的口服生物利用度会大大增加。然而,绝大多数CYP 3A抑制剂具有一定的药理活性和临床适应症,这些物质在体内需要达到一定的浓度才能发挥抑制CYP 3A酶活性的作用,这样就会产生毒副作用,限制了其在临床上的进一步应用。但联用CYP 3A抑制剂可提高CYP 3A底物药物的口服吸收及生物利用度,因此寻找一些无药理活性、低毒且具有较强CYP 3A抑制作用的抑制剂是国内外生物药剂学学者重点研究的领域之一。
药物辅料一直被认为是生理惰性的物质而应用于各种制剂中,近几年国内外研究者陆续发现某些制剂辅料(特别是非离子表面活性剂)具有抑制CYP3A的活性,从而改变药物在体内的吸收、分布、代谢、排泄过程。利用对CYP 3A有抑制作用的辅料构建载体给药系统,可降低CYP 3A底物药物在胃肠道吸收过程中被CYP 3A所氧化代谢的程度,提高CYP 3A底物药物的口服生物利用度；同时也不会产生新的毒副作用。因此从给药系统的角度来提高CYP 3A底物药物的口服生物利用度,较其它的策略更为可靠、易行,具有广泛的应用开发前景。
为了考察包含有对CYP 3A有抑制作用的辅料构建的载体给药系统对CYP 3A酶的影响,以咪达唑仑(MDZ)为模型药物、选用对大鼠肝微粒体CYP 3A有明显抑制作用的表面活性剂(Cremophor EL35、Cremophor RH40、Tween-80)为主要的载体材料,采用星点设计—效应面法优化处方,制备咪达唑仑自微乳化给药系统(MDZ—SMEDDS),基本处方为：MCT:Cremophor EL35:PG=25:50:25 (W:W:W)、MCT:Cremophor RH40:PG=25:45:30 (W:W:W)或EO:Tween-80:PG=30：45：25(W：W：W)。优化后的处方水化所形成微乳的自微乳化时间和平均粒径均符合SMEDDS制剂的要求。
通过目测法和仪器分析,以外观、粒径为主要指标,考察了介质、稀释倍数、离子强度和食物效应等对各处方自乳化速率的影响,发现各因素对MDZ-SMEDDS的自微乳化效率并无明显影响；通过对各处方所形成微乳的稳定性进行考察,发现含有Cremophor EL35的微乳在人工肠液中的稳定性较差,因此,我们不再对包含Cremophor EL35的SMEDDS进行评价；比较不同MDZ制剂在人工肠液释放情况,结果显示,将MDZ制成自微乳化给药系统可以极大提高其释放的速度和程度；稳定性试验表明,在所考察的高温、强光条件下,MDZ-SMEDDS的外观、药物含量、粒径大小、自微乳化时间均无明显变化,MDZ及其微乳的稳定性良好。
考察包含Cremophor RH40和Tween 80的SMEDDS (Cremophor RH40-based SMEDDS和Tween 80-based SMEDDS)对大鼠肝细胞CYP 3A作用,发现相对于对照组(MDZ溶液),Cremophor RH40-based SMEDDS和Tween 80-based SMEDDS在1：50到1：250的稀释范围内可明显抑制1'-OHMDZ的生成,且未产生明显的细胞毒作用；通过Western blot技术检测Cremophor RH40-based SMEDDS和Tween 80-based SMEDDS对大鼠肝细胞CYP3A酶蛋白表达的影响,研究证实,在1：50到1：100的稀释范围内包含CremophorRH40和Tween 80的SMEDDS能显著降低大鼠肝细胞中CYP 3A的蛋白表达水平,相对于对照组(生理盐水),其CYP 3A的蛋白表达量分别为40.5±9.9%和28.8±7.2%(RH40-based SMEDDS),65.3±10.8%和35.8±8.3%(Tween 80-based SMEDDS)。这些结果进一步表明,SMEDDS能抑制MDZ在大鼠肝细胞的代谢部分是由于下调了CYP3A的蛋白表达,从而减少CYP 3A酶的生物转化活性。
分别单次或多次灌胃给予大鼠生理盐水、MDZ市售片剂(Dormicum(?))、Cremophor RH40-based SMEDDS与酮康唑溶液,从大鼠肠黏膜上皮细胞提取分离肠RNA和蛋白,采用RT-PCR和Western blot技术检测肠道核酸转录水平和蛋白表达水平。结果显示,相对于生理盐水对照组,单剂量和多剂量给予Cremophor RH40-based SMEDDS微乳显著降低了大鼠肠黏膜上皮细胞中CYP 3A的mRNA表达水平(见图6-1),mRNA表达量分别为生理盐水对照组57.3±5.6%(单剂量)和57.6±7.7%(多剂量),而Dormicum(?)片剂混悬液对大鼠肠道CYP 3A的mRNA表达水平并无明显的影响,mRNA表达量分别为对照组98.3±7.3%(单剂量)和90.6±7.8%(多剂量)。Western blot检测结果与RT-PCR一致,单剂量和多剂量给予Cremophor RH40-based SMEDDS微乳显著降低了大鼠肠黏膜上皮细胞中CYP3A的蛋白表达水平(P<0.05),蛋白表达量分别为生理盐水对照组53.7±6.9%(单剂量)和40.2±8.5%(多剂量)；单剂量给予Dormicum(?)片剂混悬液对大鼠肠道CYP3A的蛋白表达水平并无明显的影响,而多剂量给予Dormicum(?)片剂混悬液却轻微降低了大鼠肠道CYP3A的蛋白表达水平,蛋白表达量分别为对照组89.5±10.8%(单剂量)和76.8±16.1%(多剂量)。上述结果说明单剂量或多剂量给予Cremophor RH40-based SMEDDS,都会降低大鼠肠道CYP 3A酶的基因表达水平,从而提高CYP3A底物药物MDZ的口服生物利用度。
分别单次或多次灌胃给予大鼠MDZ市售片剂(Dormicum(?))、Cremophor RH40-based SMEDDS与Tween 80-based SMEDDS.结果显示,相对于市售片剂,单剂量和多剂量给予Cremophor RH40-based SMEDDS微乳与Tween 80-based SMEDDS微乳后,MDZ口服生物利用度有明显提高,且显著降低了1'-OHMDZ与MDZ的AUC0-∞比值。与市售Dormicum(?)片剂组的AUC0-∞比较,单剂量和多剂量给予Tween 80-basedSMEDDS的相对生物利用度分别为(226.51±43.38)%和(246.11±44.71)%；Cremophor RH40-based SMEDDS的相对生物利用度分别为(314.38±107.56)%和(332.74±82.97)%(P<0.05),AUC0-∞1'-OHMDZ／AUC0-∞MDZ的比值分别从0.25降至0.14(Tween 80-based SMEDDS)和0.11(Cremophor RH40-based SMEDDS)(单剂量),以及从0.27降至0.12 (Tween 80-based SMEDDS)和0.09(Cremophor RH40-based SMEDDS)(多剂量)；同时Cremophor RH40-based SMEDDS微乳与Tween 80-based SMEDDS微乳也显著降低了MDZ的清除率(CL)并延长了MDZ在体内的平均滞留时间(MRT)及消除半衰期(t1／2)。
综上所述,包含有对CYP3A有抑制作用的辅料构建载体系统可有效的保护CYP3A底物药物的代谢,从而提高其口服生物利用。通过研究包含有对CYP 3A有抑制作用的辅料构建载体系统对CYP 3A酶的影响,从而为提高某些药物口服吸收而设计高口服生物利用度新剂型提供理论依据；为临床低生物利用度药物的疗效提高提供一条新的途径。因此,本研究具有重要的理论意义和现实意义。
Oral absorption of a drug involves complicated processes and varies with formulation factors and physiological conditions (solubility, tissue permeability, formulation factors etc.). However, inhibiting cytochrome P450 3A (CYP3A) activity is considered to be a helpful strategy for enhancing absorption of orally administered drugs that may be oxidized by CYP3A. CYP3A localizing in both the liver and intestine, and accounts for 30% of the total P450 content in the adult liver and for 70% in the intestine. CYP3A is involved in the metabolism of more than 50% of the currently marketed drugs and make a major contribution to the presystemic elimination of substrate drugs after oral administration.
Indeed, it has been previously reported that inhibition of CYP3A enzymes by various compounds can lead to increased bioavailability of drugs. However, most of these inhibitory compounds are pharmacologically active ingredients and have their own clinical indications. Furthermore, most of these inhibitors lead to undesired pharmacodynamic side effects caused by the high concentrations necessary for sufficient gastrointestinal inhibition of CYP3A, which limits its clinical efficacy. But in combination of CYP 3A inhibitors can increase the oral absorption and bioavailability of CYP 3A substrate drugs, seeking for some strong CYP 3A inhibitors with properties of non-pharmacological activity and low toxicity is one of the most important research fields in biopharmaceutics.
More recently, concerns have been raised that some excipients, especially nonionic surfactants, may also influence the absorption, distribution, metabolism and elimination of the active drugs by inhibiting CYP3A enzymes in vivo. Drug delivery system constructed with the inhibitors of CYP3A can reduce the extent of oxidative metabolism and improve the oral bioavailability of CYP3A substrate drugs in the gastrointestinal absorption process. For the perspective of drug delivery systems, improvement of the oral bioavailability of CYP 3A substrate drugs can be more reliable and easier than other strategies and have a wide range of development prospects.
In order to investigate the effects of a drug delivery system constructed with excipient inhibitors on the CYP 3A enzymes, midazolam (MDZ) was selected as a model drug and the surface surfactants (Cremophor EL35, Cremophor RH40, Tween-80) which significantly inhibited CYP 3A enzymes in rat liver microsomes were the main formulation components. Central composite design-response surface methodology was used to optimize the preparation of MDZ-based self-microemulsifying drug delivery system (MDZ-SMEDDS). Basic prescription for the SMEDDS were:MCT:Cremophor EL35:PG =25:50:25 (W:W:W)、MCT:Cremophor RH40:PG=25:45:30 (W:W:W) or EO: Tween-80:PG=30:45:25 (W:W:W). The optimized microemulsion formulation formed from hydration self-microemulsifying time and the average particle size met the requirements of SMEDDS preparation.
Visual assessment and instrumental analysis were not found to have significant effect on the self-microemulsifying efficiency in various factors of medium、dilution times、ionic strength and food effects. In the stability study, formulation containing Cremophor EL35 in simulated intestinal juice was dissolved from 378μg/mL at 10min to 245μg/mL at 180min. Formulation containing Cremophor EL35 could not prevent MDZ precipitation in the presence of aqueous phase as efficiently as other formulation. It has been known from the reproted literature that, surfactant hydrolysis may have a negative impact on the overall solubilization capacity of self-microemulsifying formulation containing large amounts of digestible surfactants. Cremophor EL35 and Cremophor RH40 have similar chemical structure. Interestingly, however, Cremophor RH40 appeared to be less susceptible to digestion when compared with EL35 in vitro digestion experiments. Thus, in the presence of the Cremophor EL 35, the ability to prevent precipitation seems to be reduced. On the basis of these findings, formulation containing Cremophor EL35 was excluded from further evaluation. The comparison results of release profile of different MDZ formulations showed that self-microemulsifying drug delivery system can greatly improve the speed and extent of MDZ released. Stability test showed that the appearance, drug content, particle size, and self-microemulsifying time were not significantly changed in the high temperature and strong light conditions.
We evaluated the effects of SMEDDS contains Cremophor RH40 and Tween 80 (Cremophor RH40-based SMEDDS and Tween 80-based SMEDDS) at different dilution times on the metabolism of MDZ in rat hepatocytes. The results showed that the metabolism of MDZ was significantly inhibited in the dilution range from 1:50 to 1:250 without causing cell cytotoxicity. In west blot analysis, a significant decrease in CYP3A protein levels was observed in cells in the presence of either Cremophor RH40 or Tween 80-based SMEDDS in the dilution range from 1:50 to 1:100 compared to control (P<0.05),40.5±9.9% and 28.8±7.2% of control (for RH40-based SMEDDS),65.3±10.8% and 35.8±8.3% of control (for Tween 80-based SMEDDS), respectively. These results suggest that the Tween 80 or Cremophor RH40-based SMEDDS may inhibit MDZ metabolism by down-regulating the CYP3A protein expression, which decreases the catalytic activity of CYP3A enzymes.
To clarify the mechanism of inhibition of SMEDDS on CYP3A enzymes, the effects of the saline、the commercial tablet of MDZ (Dormicum(?))、Cremophor RH40-based SMEDDS and ketoconazole (KTZ) solution on the intestinal CYP3A enzymes mRNA and protein level in rats following single-dose and multiple-dose administration were assessed by RT-PCR and Western blot analyses. The results showed that Cremophor RH40 significantly decreased the levels of CYP 3A mRNA and protein expression in mucosa of rats versus the saline control group; 57.3±5.6% of control (for single-dose group),57.6±7.7% of control (for multiple-dose group), respectively There were no significant difference in CYP3A mRNA levels among Dormicum(?) group,98.3±7.3% of control (for single-dose group),90.6±7.8% of control (for multiple-dose group). Consistent with this observation, the expression of CYP3A protein was significantly decreased,53.7±6.9% of control (for single-dose group),40.2±8.5% of control (for multiple-dose group), respectively. There were no significant difference in CYP3A mRNA levels among Dormicum(?) group, These results further support the result that the Cremophor RH40-based SMEDDS may inhibit MDZ metabolism partially due to down-regulating the CYP3A mRNA and protein expression, which further decrease the catalytic activity of CYP3A enzymes.
We assessed the effects of the commercial tablet of MDZ (Dormicum(?))、Cremophor RH40-based SMEDDS and Tween 80-based SMEDDS on the pharmacokinetics of MDZ and its metabolite 1'-Hydroxymidazolam in rats following single-dose and multiple-dose administration, the results showed that the oral bioavailability of MDZ microemulsion of Cremophor RH40-based SMEDDS and Tween 80-based SMEDDS was greater than that of the commercial tablet. The relative bioavailability were (226.51±43.38)%(single-dose group) and (246.11±44.71)%(multiple-dose group) for Tween 80-based SMEDDS; (314.38±107.56)%(single-dose group) and (332.74±82.97)%(multiple-dose group) for Cremophor RH40-based SMEDDS. Furthermore, MDZ microemulsion significantly decreased the ratio of AUC0-∞(1'-OH-MDZ)/AUC0-∞(MDZ), from 0.25 to 0.14 (Tween 80-based SMEDDS) and 0.11 (Cremophor RH40-based SMEDDS) for single-dose group; from 0.27 to 0.12 (Tween 80-based SMEDDS) and 0.09 (Cremophor RH40-based SMEDDS) for single-dose group, and reduced the clearance (CL) of MDZ. Moreover the MRT and elimination half-time (t1/2) were also increased by MDZ microemulsion in the single-dose and multiple-dose regimen.
In summary, the excipient inhibitor-based formulation is a potential protective platform for decreasing metabolism of sensitive drugs that are CYP3A substrates. This study can provide a theoretical basis for the design of the new formulation to improve the low bioavailability drug, and therefore has an important theoretical and practical significance.
有文献报道,易被CYP 3A酶代谢的药物与CYP 3A抑制剂共同服用,这些药物的口服生物利用度会大大增加。然而,绝大多数CYP 3A抑制剂具有一定的药理活性和临床适应症,这些物质在体内需要达到一定的浓度才能发挥抑制CYP 3A酶活性的作用,这样就会产生毒副作用,限制了其在临床上的进一步应用。但联用CYP 3A抑制剂可提高CYP 3A底物药物的口服吸收及生物利用度,因此寻找一些无药理活性、低毒且具有较强CYP 3A抑制作用的抑制剂是国内外生物药剂学学者重点研究的领域之一。
药物辅料一直被认为是生理惰性的物质而应用于各种制剂中,近几年国内外研究者陆续发现某些制剂辅料(特别是非离子表面活性剂)具有抑制CYP3A的活性,从而改变药物在体内的吸收、分布、代谢、排泄过程。利用对CYP 3A有抑制作用的辅料构建载体给药系统,可降低CYP 3A底物药物在胃肠道吸收过程中被CYP 3A所氧化代谢的程度,提高CYP 3A底物药物的口服生物利用度；同时也不会产生新的毒副作用。因此从给药系统的角度来提高CYP 3A底物药物的口服生物利用度,较其它的策略更为可靠、易行,具有广泛的应用开发前景。
为了考察包含有对CYP 3A有抑制作用的辅料构建的载体给药系统对CYP 3A酶的影响,以咪达唑仑(MDZ)为模型药物、选用对大鼠肝微粒体CYP 3A有明显抑制作用的表面活性剂(Cremophor EL35、Cremophor RH40、Tween-80)为主要的载体材料,采用星点设计—效应面法优化处方,制备咪达唑仑自微乳化给药系统(MDZ—SMEDDS),基本处方为：MCT:Cremophor EL35:PG=25:50:25 (W:W:W)、MCT:Cremophor RH40:PG=25:45:30 (W:W:W)或EO:Tween-80:PG=30：45：25(W：W：W)。优化后的处方水化所形成微乳的自微乳化时间和平均粒径均符合SMEDDS制剂的要求。
通过目测法和仪器分析,以外观、粒径为主要指标,考察了介质、稀释倍数、离子强度和食物效应等对各处方自乳化速率的影响,发现各因素对MDZ-SMEDDS的自微乳化效率并无明显影响；通过对各处方所形成微乳的稳定性进行考察,发现含有Cremophor EL35的微乳在人工肠液中的稳定性较差,因此,我们不再对包含Cremophor EL35的SMEDDS进行评价；比较不同MDZ制剂在人工肠液释放情况,结果显示,将MDZ制成自微乳化给药系统可以极大提高其释放的速度和程度；稳定性试验表明,在所考察的高温、强光条件下,MDZ-SMEDDS的外观、药物含量、粒径大小、自微乳化时间均无明显变化,MDZ及其微乳的稳定性良好。
考察包含Cremophor RH40和Tween 80的SMEDDS (Cremophor RH40-based SMEDDS和Tween 80-based SMEDDS)对大鼠肝细胞CYP 3A作用,发现相对于对照组(MDZ溶液),Cremophor RH40-based SMEDDS和Tween 80-based SMEDDS在1：50到1：250的稀释范围内可明显抑制1'-OHMDZ的生成,且未产生明显的细胞毒作用；通过Western blot技术检测Cremophor RH40-based SMEDDS和Tween 80-based SMEDDS对大鼠肝细胞CYP3A酶蛋白表达的影响,研究证实,在1：50到1：100的稀释范围内包含CremophorRH40和Tween 80的SMEDDS能显著降低大鼠肝细胞中CYP 3A的蛋白表达水平,相对于对照组(生理盐水),其CYP 3A的蛋白表达量分别为40.5±9.9%和28.8±7.2%(RH40-based SMEDDS),65.3±10.8%和35.8±8.3%(Tween 80-based SMEDDS)。这些结果进一步表明,SMEDDS能抑制MDZ在大鼠肝细胞的代谢部分是由于下调了CYP3A的蛋白表达,从而减少CYP 3A酶的生物转化活性。
分别单次或多次灌胃给予大鼠生理盐水、MDZ市售片剂(Dormicum(?))、Cremophor RH40-based SMEDDS与酮康唑溶液,从大鼠肠黏膜上皮细胞提取分离肠RNA和蛋白,采用RT-PCR和Western blot技术检测肠道核酸转录水平和蛋白表达水平。结果显示,相对于生理盐水对照组,单剂量和多剂量给予Cremophor RH40-based SMEDDS微乳显著降低了大鼠肠黏膜上皮细胞中CYP 3A的mRNA表达水平(见图6-1),mRNA表达量分别为生理盐水对照组57.3±5.6%(单剂量)和57.6±7.7%(多剂量),而Dormicum(?)片剂混悬液对大鼠肠道CYP 3A的mRNA表达水平并无明显的影响,mRNA表达量分别为对照组98.3±7.3%(单剂量)和90.6±7.8%(多剂量)。Western blot检测结果与RT-PCR一致,单剂量和多剂量给予Cremophor RH40-based SMEDDS微乳显著降低了大鼠肠黏膜上皮细胞中CYP3A的蛋白表达水平(P<0.05),蛋白表达量分别为生理盐水对照组53.7±6.9%(单剂量)和40.2±8.5%(多剂量)；单剂量给予Dormicum(?)片剂混悬液对大鼠肠道CYP3A的蛋白表达水平并无明显的影响,而多剂量给予Dormicum(?)片剂混悬液却轻微降低了大鼠肠道CYP3A的蛋白表达水平,蛋白表达量分别为对照组89.5±10.8%(单剂量)和76.8±16.1%(多剂量)。上述结果说明单剂量或多剂量给予Cremophor RH40-based SMEDDS,都会降低大鼠肠道CYP 3A酶的基因表达水平,从而提高CYP3A底物药物MDZ的口服生物利用度。
分别单次或多次灌胃给予大鼠MDZ市售片剂(Dormicum(?))、Cremophor RH40-based SMEDDS与Tween 80-based SMEDDS.结果显示,相对于市售片剂,单剂量和多剂量给予Cremophor RH40-based SMEDDS微乳与Tween 80-based SMEDDS微乳后,MDZ口服生物利用度有明显提高,且显著降低了1'-OHMDZ与MDZ的AUC0-∞比值。与市售Dormicum(?)片剂组的AUC0-∞比较,单剂量和多剂量给予Tween 80-basedSMEDDS的相对生物利用度分别为(226.51±43.38)%和(246.11±44.71)%；Cremophor RH40-based SMEDDS的相对生物利用度分别为(314.38±107.56)%和(332.74±82.97)%(P<0.05),AUC0-∞1'-OHMDZ／AUC0-∞MDZ的比值分别从0.25降至0.14(Tween 80-based SMEDDS)和0.11(Cremophor RH40-based SMEDDS)(单剂量),以及从0.27降至0.12 (Tween 80-based SMEDDS)和0.09(Cremophor RH40-based SMEDDS)(多剂量)；同时Cremophor RH40-based SMEDDS微乳与Tween 80-based SMEDDS微乳也显著降低了MDZ的清除率(CL)并延长了MDZ在体内的平均滞留时间(MRT)及消除半衰期(t1／2)。
综上所述,包含有对CYP3A有抑制作用的辅料构建载体系统可有效的保护CYP3A底物药物的代谢,从而提高其口服生物利用。通过研究包含有对CYP 3A有抑制作用的辅料构建载体系统对CYP 3A酶的影响,从而为提高某些药物口服吸收而设计高口服生物利用度新剂型提供理论依据；为临床低生物利用度药物的疗效提高提供一条新的途径。因此,本研究具有重要的理论意义和现实意义。
Oral absorption of a drug involves complicated processes and varies with formulation factors and physiological conditions (solubility, tissue permeability, formulation factors etc.). However, inhibiting cytochrome P450 3A (CYP3A) activity is considered to be a helpful strategy for enhancing absorption of orally administered drugs that may be oxidized by CYP3A. CYP3A localizing in both the liver and intestine, and accounts for 30% of the total P450 content in the adult liver and for 70% in the intestine. CYP3A is involved in the metabolism of more than 50% of the currently marketed drugs and make a major contribution to the presystemic elimination of substrate drugs after oral administration.
Indeed, it has been previously reported that inhibition of CYP3A enzymes by various compounds can lead to increased bioavailability of drugs. However, most of these inhibitory compounds are pharmacologically active ingredients and have their own clinical indications. Furthermore, most of these inhibitors lead to undesired pharmacodynamic side effects caused by the high concentrations necessary for sufficient gastrointestinal inhibition of CYP3A, which limits its clinical efficacy. But in combination of CYP 3A inhibitors can increase the oral absorption and bioavailability of CYP 3A substrate drugs, seeking for some strong CYP 3A inhibitors with properties of non-pharmacological activity and low toxicity is one of the most important research fields in biopharmaceutics.
More recently, concerns have been raised that some excipients, especially nonionic surfactants, may also influence the absorption, distribution, metabolism and elimination of the active drugs by inhibiting CYP3A enzymes in vivo. Drug delivery system constructed with the inhibitors of CYP3A can reduce the extent of oxidative metabolism and improve the oral bioavailability of CYP3A substrate drugs in the gastrointestinal absorption process. For the perspective of drug delivery systems, improvement of the oral bioavailability of CYP 3A substrate drugs can be more reliable and easier than other strategies and have a wide range of development prospects.
In order to investigate the effects of a drug delivery system constructed with excipient inhibitors on the CYP 3A enzymes, midazolam (MDZ) was selected as a model drug and the surface surfactants (Cremophor EL35, Cremophor RH40, Tween-80) which significantly inhibited CYP 3A enzymes in rat liver microsomes were the main formulation components. Central composite design-response surface methodology was used to optimize the preparation of MDZ-based self-microemulsifying drug delivery system (MDZ-SMEDDS). Basic prescription for the SMEDDS were:MCT:Cremophor EL35:PG =25:50:25 (W:W:W)、MCT:Cremophor RH40:PG=25:45:30 (W:W:W) or EO: Tween-80:PG=30:45:25 (W:W:W). The optimized microemulsion formulation formed from hydration self-microemulsifying time and the average particle size met the requirements of SMEDDS preparation.
Visual assessment and instrumental analysis were not found to have significant effect on the self-microemulsifying efficiency in various factors of medium、dilution times、ionic strength and food effects. In the stability study, formulation containing Cremophor EL35 in simulated intestinal juice was dissolved from 378μg/mL at 10min to 245μg/mL at 180min. Formulation containing Cremophor EL35 could not prevent MDZ precipitation in the presence of aqueous phase as efficiently as other formulation. It has been known from the reproted literature that, surfactant hydrolysis may have a negative impact on the overall solubilization capacity of self-microemulsifying formulation containing large amounts of digestible surfactants. Cremophor EL35 and Cremophor RH40 have similar chemical structure. Interestingly, however, Cremophor RH40 appeared to be less susceptible to digestion when compared with EL35 in vitro digestion experiments. Thus, in the presence of the Cremophor EL 35, the ability to prevent precipitation seems to be reduced. On the basis of these findings, formulation containing Cremophor EL35 was excluded from further evaluation. The comparison results of release profile of different MDZ formulations showed that self-microemulsifying drug delivery system can greatly improve the speed and extent of MDZ released. Stability test showed that the appearance, drug content, particle size, and self-microemulsifying time were not significantly changed in the high temperature and strong light conditions.
We evaluated the effects of SMEDDS contains Cremophor RH40 and Tween 80 (Cremophor RH40-based SMEDDS and Tween 80-based SMEDDS) at different dilution times on the metabolism of MDZ in rat hepatocytes. The results showed that the metabolism of MDZ was significantly inhibited in the dilution range from 1:50 to 1:250 without causing cell cytotoxicity. In west blot analysis, a significant decrease in CYP3A protein levels was observed in cells in the presence of either Cremophor RH40 or Tween 80-based SMEDDS in the dilution range from 1:50 to 1:100 compared to control (P<0.05),40.5±9.9% and 28.8±7.2% of control (for RH40-based SMEDDS),65.3±10.8% and 35.8±8.3% of control (for Tween 80-based SMEDDS), respectively. These results suggest that the Tween 80 or Cremophor RH40-based SMEDDS may inhibit MDZ metabolism by down-regulating the CYP3A protein expression, which decreases the catalytic activity of CYP3A enzymes.
To clarify the mechanism of inhibition of SMEDDS on CYP3A enzymes, the effects of the saline、the commercial tablet of MDZ (Dormicum(?))、Cremophor RH40-based SMEDDS and ketoconazole (KTZ) solution on the intestinal CYP3A enzymes mRNA and protein level in rats following single-dose and multiple-dose administration were assessed by RT-PCR and Western blot analyses. The results showed that Cremophor RH40 significantly decreased the levels of CYP 3A mRNA and protein expression in mucosa of rats versus the saline control group; 57.3±5.6% of control (for single-dose group),57.6±7.7% of control (for multiple-dose group), respectively There were no significant difference in CYP3A mRNA levels among Dormicum(?) group,98.3±7.3% of control (for single-dose group),90.6±7.8% of control (for multiple-dose group). Consistent with this observation, the expression of CYP3A protein was significantly decreased,53.7±6.9% of control (for single-dose group),40.2±8.5% of control (for multiple-dose group), respectively. There were no significant difference in CYP3A mRNA levels among Dormicum(?) group, These results further support the result that the Cremophor RH40-based SMEDDS may inhibit MDZ metabolism partially due to down-regulating the CYP3A mRNA and protein expression, which further decrease the catalytic activity of CYP3A enzymes.
We assessed the effects of the commercial tablet of MDZ (Dormicum(?))、Cremophor RH40-based SMEDDS and Tween 80-based SMEDDS on the pharmacokinetics of MDZ and its metabolite 1'-Hydroxymidazolam in rats following single-dose and multiple-dose administration, the results showed that the oral bioavailability of MDZ microemulsion of Cremophor RH40-based SMEDDS and Tween 80-based SMEDDS was greater than that of the commercial tablet. The relative bioavailability were (226.51±43.38)%(single-dose group) and (246.11±44.71)%(multiple-dose group) for Tween 80-based SMEDDS; (314.38±107.56)%(single-dose group) and (332.74±82.97)%(multiple-dose group) for Cremophor RH40-based SMEDDS. Furthermore, MDZ microemulsion significantly decreased the ratio of AUC0-∞(1'-OH-MDZ)/AUC0-∞(MDZ), from 0.25 to 0.14 (Tween 80-based SMEDDS) and 0.11 (Cremophor RH40-based SMEDDS) for single-dose group; from 0.27 to 0.12 (Tween 80-based SMEDDS) and 0.09 (Cremophor RH40-based SMEDDS) for single-dose group, and reduced the clearance (CL) of MDZ. Moreover the MRT and elimination half-time (t1/2) were also increased by MDZ microemulsion in the single-dose and multiple-dose regimen.
In summary, the excipient inhibitor-based formulation is a potential protective platform for decreasing metabolism of sensitive drugs that are CYP3A substrates. This study can provide a theoretical basis for the design of the new formulation to improve the low bioavailability drug, and therefore has an important theoretical and practical significance.
引文
1. Shimada T., Yamazaki H., Mimura M., et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals:studies with liver microsomes of 30 Japanese and 30 Caucasians[J]. J Pharmcol Exp Ther,1994,270(l):414-423.
2. Zhang Q.Y., Dunbar D., Ostrowska A., et al.Characterization of human small intestinal cytochromes P-450[J]. Drug Metab Dispos,1999,27 (7):804-809.
3. Hsing S., Gatmaitan Z., Arias I.M. The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa[J]. Gastroenterology,1992, 102(3):879-885.
4. Terao T., Hisanaga E., Sai Y., et al. Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier[J]. J Pharm Pharmacol,1996,48(10):1083-1089.
5. Cummins C.L., Jacobsen W., Benet L.Z. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4[J]. J Pharmcol Exp Ther,2002, 300(3):1036-1045.
6. Ogasawara A., Utoh M., Nii K., et al. Effect of oral ketoconazole on oral and intravenous pharmacokinetics of simvastatin and its acid in cynomolgus monkeys[J]. Drug Metab Dispos,2009,37(1):122-128.
7. Krishna G., Moton A., Ma L., et al. Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam:a phase Ⅰ, randomized, open-label, crossover study in healthy volunteers[J]. Clin Ther,2009,31(2):286-98.
8. Goldwater D.R., Dougherty C., Schumacher M., et al. Effect of ketoconazole on the pharmacokinetics of maribavir in healthy adults[J]. Antimicrob Agents Chemother, 2008,52(5):1794-1798.
9. Ridtitid W., Ratsamemonthon K., Mahatthanatrakul W., et al. Pharmacokinetic interaction between ketoconazole and praziquantel in healthy volunteers[J]. J Clin Pharm Ther,2007,32(6):585-593.
10. Ohno Y, Hisaka A., Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs[J]. Clin Pharmacokinet,2007,46(8):681-696.
11. Okamoto J., Fukunami M., Kioka H. Frequent premature ventricular contractions induced by itraconazole[J]. Circ J,2007,71(8):1323-1325.
12. Skov M., Main K.M., Sillesen I.B., et al. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide[J]. Eur Respir J, 2002,20(1):127-133.
13. Reif S., Kingreen D., Kloft C., et al. Bioequivalence investigation of high-dose etoposide and etoposide phosphate in lymphoma patients[J]. Cancer Chemother Pharmacol,2001,48(2):134-140.
14. Choi C.H., Kim J.H., Kim S.H. Reversal of P-glycoprotein-mediated MDR by 5,7,3',4',5'-pentamethoxyflavone and SAR[J]. Biochem Biophy Res commomm,2004, 320(3):672-679.
15. Bravo Gonzalez R.C., Huwyler J., Boess F., et al. In vitro investigation on the impact of the surface-active excipients Cremophor EL, Tween 80 and Solutol HS 15 on the metabolism of midazolam[J]. Biopharm Drug Dispos,2004,25(1):37-49.
16. Lipinski C.J. Poor aqueous solubility-an industry wide problem in drug discovery[J]. Am Pharm Rev,2002,5(1):82-85.
17. Kim R.B., Wandel C., Leake B., et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein[J]. Pharm Res,1999,16(3):408414.
18. Ren X.H., Si L.Q., Li G., et al. Pharmaceutical Excipients Inhibit Cytochrome P450 Activity in Cell Free Systems and After Systemic Administration[J]. Eur J Pharm Biopharm,2008,70(1):279-288.
19. Gursoy R.N., Benita S. Self-emulsifying drug delivery systems(SEDDS) for improved oral delivery of lipophilic drug[J]. Biomed Pharmacother,2004,58(3):173-182.
20. Bravo-Gonzalez R.C., Huwyler J., Walter I., et al. Improved oral bioavailability of cyclosporine A in male wistar rats. comparison of a solutol HS 15 containing
self-dispersing formulation and a microsuspension[J]. Int J Pharm,2002, 245(1-2):143-151.
21.平其能,胡一桥,周建平.现代药剂学[M].北京：中国医药工业出版社,2001年.
22. Ranaldi G., Consalvo R., Sambuy Y., et al. Permeability characteristics of parental and clonal human intestinal Caco-2 cell lines differentiated in serum-supplemented and serum-free media[J]. Toxicology in Vitro,2003,17(5):761-767.
23. Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man-fact or myth[J]. Pharm Res,1997,14(6):763-766.
24.郭勇,郑穗平.酶学[M].广州：华南理工大学出版社,2000年.
25. Cotreau M.M., von Moltke L.L., Beinfeld M.C., et al. Methodologies to study the induction of rat hepatic and intestinal cytochrome P450 3A at the mRNA, protein and catalytic activity level[J]. J Pharmacol Toxicol Methods,2000,43(1):41-54.
26. Bradford M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding[J]. Anal Biochem, 1976,2:248-254.
27.李高,陈鹰,王瑞华.长春西汀自微乳化给药系统的研究[J].中国药学杂志,2006,41(23)：1795-1799.
28. Kim R.B., Wandel C., Leake B., et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein[J]. Pharm Res,1999,16(3):408-414.
29. Benet L.Z., Cummins C.L. The drug efflux-metabolism alliance:biochemical aspect[J]. Adv Drug Deliv Rev,2001,50(sup 1):S3-S11.
30. Polli J.W., Wring S.A., Humphreys J.E., et al. Rational use of in vitro P-glycoprotein assays in drug discovery[J]. J Pharmacol Exp Ther,2001,299(2):620-628.
31. Wandel C., Bocker R., Bohrer H., et al. Midazolam is metabolized by at least three different cytochrome P450 enzymes[J]. Br J Anaesth,1994,75(3):658-661.
32. Fumico H., Teruo M., Tatsuya K., et al. Dose-dependent intestinal and hepatic first-pass metabolism of midazolam, a cytochrome P450 3A substrate with differently modulated enzyme activity in rats[J]. J. Pharm. Pharmacol.,1999,51(1):67-72.
33. Eeckhoudt S.L., Horsmans Y., Verbeeck R.K. Differential induction of midazolam metabolism in the small intestine and liver by oral and intravenous dexamethasone pretreatment in rat[J]. Xenobiotica,2001,32(11):975-984.
34. Ribeiro V., Lechner M.C. Cloning and characterization of a novel CYP3A1 allelic variant:analysis of CYP3A1 and CYP3A2 sex-hormone-dependent expression reveals that the CYP3A2 gene is regulated by testosterone[J]. Arch Biochem Biophys,1992, 293(1):147-152.
35. Chen M.L. Lipid excipients and delivery systems for pharmaceutical development:A regulatory perspective[J]. Adv Drug Deliv Reviews,2008,60:768-777.
36. Jin M., Shimada T., Yokogawa K., et al. Cremophor EL releases cyclosporine A adsorbed on blood cells and blood vessels, and increases apparent plasma concentration of cyclosporine A[J]. Int J Pharm,2005,293(1-2):137-144.
37. Scott Obach R., Reed-hagen A.E.. Measurement of michaelis constantants for cytochrome P450-mediated bioransformation reactions using a substrate depletion approach[J]. Drug Metab. Dispos.,2002,30(7):831-837.
38. Mountfield R.J., Senepin S., Schleimer M., et al. Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450[J]. Int J Pharm,2000, 211(1-2):89-92.
39. Gershanik T., Haltner E., Lehr C.M., et al. Charge-dependent interaction of self-emulsifying oil formulations with Caco-2 cell monolayers:binding, effects on barrier function and cytotoxicity[J]. Int J Pharm,2000,211(1-2):29-36
40. Tarr B.D., Yalkowsky S.H. Enhanced intestinal absorption of cyclosporine in rats through the reduction of emulsion droplet size[J]. Pharm Res,1989,6(1):40-43
41. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption:physical and biopharmaceutical aspects[J]. Pharm Res,1995,12(11): 1561-1572.
42. Okonogi S., Oguchi T., Yonemochi E., et al. Improved dissolution of ofloxacin via solid dispersion[J]. Int J Pharm,1997,156(2):175-180.
43. Yoo S.D., Lee S.H., Kang E., et al. Bioavailability of itraconazole in rats and rabbits after administration of tablets containing solid dispersion particles[J]. Drug Dev Ind Pharm,2000,26(1):27-34.
44. Shui M., Andrew J., Christopher J. Formulation design and bioavailability assessment of lipidic self-emulsifying formulation of halofantrine[J]. Int J Pharm,1998,167(1-2): 155-164.
45.涂秋榕,朱颖,朱家璧.尼莫地平自微乳化液的处方研究[J].中国药学杂志,2005,40(3)：43-46.
46.吴伟崔光华.星点设计—效应面优化法及其在药学中的应用[J].国外医学药学分册,2000,27(5)：292-299.
47.陆彬吴伟.中心多点等距设计法优化醋酸地塞米松聚丙交酯微球的制备工艺[J].药学学报,1999,34(5)：387-391.
48.郑俊民主译药用辅料手册[M].第四版,北京：化学工业出版社,2005年.
49. Gershanik T., Benzeno S., Benita S., et al. Interaction of a self-emulsifying lipid drug delivery system with the everted rat intestinal mucosa as a function of droplet size and surface charge[J]. Pharm. Res.,1998,15(6):863-869.
50. Gershanik T., Benita S. Positively charged self-emulsifying oil formulation for improving oral bioavailability of progesterone[J]. Pharm. Dev. Technol.,1996,1(2): 147-157.
51. Holm R., Porter C.J.H., Edwards G.A., et al. Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery containing structured triglycerides[J]. Eur. J. Pharm. Sci.,2003,20(2):90-97.
52.张学农,唐丽华,阎雪莹,等.紫杉醇自乳化微乳的制备及其在大鼠体内的药动学[J].中国新药与临床杂志,2005,24(4)：294-298.
53.凌桂霞,孙进,殷静,等.桂利嗪自微乳化软胶囊的制备和溶出度的考察[J].中国药学杂志,2005,40(19)：1452-1454.
54. Shah N.H., Canajal M.T., Patel C.I., et al. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs[J]. Int J Pharm,1994,106(1):15-23.
55. Kang B.K., Lee J.S., Chon S.K., et al. Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs[J]. Int J Pharm,2004,274(1-2):65-73.
56. Wakerly M.C.P., Pouton C.W., Meakin B.J. Evaluation of the self-emulsifying performance of a non-ionic surfactant-vegetable oil mixture[J]. J Pharm Pharmacol, 1987,39(1):6P-6P.
57. Craig D.Q.M., Barker S.A., Banning D., et al. An investigation into the mechanisms of self -emulsification using particle size analysis and low frequency dielectric spectroscopy[J]. Int J Pharm,1995,114(1):103-110.
58. Kommuru T.R., Gurley B., Khan M.A., et al. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10:formulation development and bioavailability assessment[J]. Int J Pharm,2001,212(1):233-246.
59. Pouton C.W. Formulation of self-emulsifying drug delivery systems [J]. Adv Drug Deliv Reviews,1997,25(1):47-58.
60. Giannakou SA., Dallas PP., Rekkas DM., et al. In vitro evaluation of nimodipine permeation through human epidermis using response surface methodology[J]. Int J Pharm,2002,241(1):27-34.
61. Kagkadis KA., Rekkas DM., Dallas PP., et al. A freeze-dried injection form of flurbiprofen:development and optimization using response surface methodology[J]. Int J Pharm,1998,161(1):87-94.
62. Colin W.P. Self-emulsifying drug delivery systems:assessment of the efficiency of emulsification[J]. Int J Pharm,1985,27(2-3):335-348.
63. Bachynsky M.O., Shah N.H., Patel C.I., et al. Factors affecting the efficiency of a self-emulsifying oral delivery system[J]. Drug Deve Ind Pharm.,1997,23(8):809-816.
64. Gershanik T., Benzeno S., Beniton S. Interaction of self-emulsifying lipid drug delivery system with the everted rat intestinal macosa as a fuction of droplet size and
surface charge[J]. Pharm Res,1998,15(6):863-869.
65. Pouton C.W. Lipid formulation for oral administration of drug:non-emulsifying, self-emulsifying and "self-microemulsifying" drug delivery systems[J]. Eur J Pharm Sci,2000, 11(suppl 2):S93-S98.
66. Trotta M.A. Affluence of phase transformation on indomethacine release of microemul sions[J]. J Control Release,1999,60(2-3):399-405.
67.王懿睿,杜光.伊曲康唑自微乳化释药系统体外释放的评价方法[J].中国医院药学杂志,2008,28(11)：877-880.
68.毕殿洲.药剂学(第三版)[M].北京：人民卫生出版社,1999年.
69. Shah N.H., Carvajal M.T., Patel C.I., et al. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drug[J]. Int J Pharm,1994,106:15-23.
70. Perlman, M.E., Murdande, S.B., Gumkowski, M.J., et al. Development of a self-emulsifying formulation that reduces the food effect for tocetrapib[J]. Int J Pharm, 2008,351(1-2):15-22.
71. Cuine J.F., Mcevoy C.L., Charman W.N., et al. Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs[J]. J Pharm Sci,2008,97(2):995-1011.
72.张莉,夏运岳.用电子表格Excel计算药物溶出度Weibull分布参数[J].药学进展,2002,26(1)：48-50.
73. Chen Y., Li G., Wu X.G., et al. Self-microemulsifying drug delivery system(SMEDDS) of vinpocetine:formulation development and in vivo assessment[J]. Biol Pharm Bull, 2008,31(1):118-125.
74. Wu W., Wang Y., Que L. Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system[J]. Eur J Pharm Biopharm,2006,63(3): 288-294.
75. Zhang P., Liu Y., Feng N.P., et al. Preparation and evaluation of self-microemulsifying drug delivery system of oridonin[J]. Int J Pharm,2008,355(1-2):269-276.
76. Nishimura, T., Amano, N., Kubo, Y., et al. Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey[J]. Drug Metab Dispos,2007,35(8):1275-1284.
77. Paine, M.F., Shen, D.D., Kunze, K.L., et al. First-pass metabolism of midazolam by the human intestine[J]. Clin Pharmacol Ther,1996,60(1):14-24.
78.赵冬梅,李燕.药物代谢研究在新药开发中的作用[J].药学学报,2000,35(2)：156-160.
79. Riordan S., Williams R. Bioartificial livers support:developments in hepatoeyte culture and bioreactor design[J]. Br Med Bull,1997,53(4):730-734.
80. Seglen PO. Preparation of isolated rat liver cells[J]. Methods Cell Biol,1976,13: 29-83.
81. Kienhuis AS et al. A sandwich-cultured rat hepatocyte system with increased metabolic competence evaluated by gene expression profiling[J]. Toxicol in Vitro,2007,21(5): 892-901.
82.薛俊峰,李桦,阮金秀,等.氮烯乙茶在成年大鼠肝细胞中的生物转化[J].药学学报,1999,34(10)：739-743
83. Lu C., Li P., Gallegos R., et al. Comparison of intrinsic clearance in liver microsomes and hepatocytes from rats and humans:evaluation of free fraction and uptake in hepatocytes[J]. Drug Metab Dispos 2006,34(9):1600-1605.
84. Wang K., Shindoh H., Tomoaki I., et al. Advantages of in vitro cytotoxicity testing by using primary rat hepatocytes in comparison with established cell lines[J]. J Toxicol Sci,2002,27(3):229-237.
85. Albert P., Human hepatocytes:Isolation,cryopreservation and applications in drug development[J]. Chem Biol Interact,2007,168(1):16-29.
86. Quattrochi L.C., Guzelian P.S. CYP3A regulation:from pharmacology to nuclear receptors[J]. Drug Metab Dispos,2001,29(5):615-622.
87. Xie W., Evans R.M. Orphan nuclear receptors:the exotics of xenobiotics[J]. J Biol Chem,2001,276(41):37739-37742.
88. Da-Silva M.E.F., Meirelles N.C. Interaction of non-ionic surfactants with hepatic CYP in prochilodus scrofa[J]. Toxicol in Vitro,2004,18(6):859-867.
89. Yun C.H., Song M., Ahn T., et al. Conformational change of cytochrome P 450 1A2 induced by sodium chloride[J]. J Biol Chem,1996,271(49):31312-31316.
90. Halpert JR. Structural basis of selective cytochrome P450 inhibition [J]. Annu Rev Pharmacol Toxicol,1995,35:29-53.
91. Aranzazu-Partearroyo M., Ostolaza H., Goni F.M., et al. Surfactant-induced cell toxicity and cell lysis. A study using B16 melanoma cells[J]. Biochem Pharmacol, 1990,40(6):1323-1328.
92. Kamm W., Jonczyk A., Jung T., et al. Evaluation of absorption enhancement for a potent cyclopeptidic αvβ3-anatgonist in a human intestinal cell line (Caco-2)[J]. Eur J Pharm Sci,2000,10(3):205-214.
93. Guengerich F.P., Martin M.V., Beaune P.H., et al. Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism [J]. J Biol Chem, 1986,261(11):5051-5060.
94. Sumida A., Kinoshita K., Fukuda T., et al. Relationship between mRNA levels quantified by reverse transcription-competitive PCR and metabolic activity of CYP3A4 and CYP2E1 in human liver[J]. Biochem Biophys Res Commun,1999, 262(2):499-503.
95. Cotreau M.M., von Moltke L.L., Beinfeld M.C., et al. Methodologies to study the induction of rat hepatic and intestinal cytochrome P450 3A at the mRNA, protein, and catalytic activity level[J]. J Pharmacol Toxicol Methods,2000,43(1):41-54.
96. Thummel KE, O'Shea D, Paine MF, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism[J]. Clin Pharmacol Ther,1996,59(5):491-502.
97. Paine MF, Shen DD, Kunze KL, et al. First pass metabolism of midazolam by the human intestine[J]. Clin Pharmacol Ther,1996,60(1):14-24.
98. Lim Y.P., Kuo S.C., Lai M.L., et al. Inhibition of CYP3A4 expression by ketoconazole is mediated by the disruption of pregnane X receptor, steroid receptor coactivator-1, and hepatocyte nuclear factor 4alpha interaction[1]. Pharmacogenet Genomics,2009,19(1): 11-24.
99. Fujita T., Yasuda S., Kamata Y., et al. Contribution of down-regulation of intestinal and hepatic cytochrome P450 3A to increased absorption of cyclosporine A in a rat nephrosis model[J]. J Pharmacol Exp Ther,2008,327(2):592-599.
100.黄林清,杨志勇.肝细胞色素P450与药物代谢的研究进展[J].中国药房,2001,12(6)：372-374.
101.Andersson T., Koivusaari U., Influence of environmental temperature on the induction of xenobiotic metabolism by β-naphoflavone in rainbow trout, Saino garidneri[J]. Toxicol Appl Phamacol,1985,80(1):45-50
102.金念祖,陆晓和.食物、细胞色素P450酶与药物代谢[J].上海环境科学,2001,20(2)：87-91.
103.骆文香,张银娣.药物代谢中的肝细胞色素P450[J].药学进展,1999,23(1)：27-33.
104.Bookout A.L., Jeong Y., Downes M., et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network[J]. Cell,2006,126(4):789-799.
105.Chawla A., Repa J J., Evans R.M., et al. Nuclear receptors and lipid physiology:opening the X-files[J]. Science,2001,294(5548):1866-1870.
106.Lee C.H., Plutzky J. Liver X receptor activation and high-density lipoprotein biology:a reversal of fortune[J]. Circulation,2006,113(1):5-8.
107.Mei Q., Richards K., Strong-Basalyga K., et al. Using real-time quantitative TaqMan RT-PCR to evaluate the role of dexamethasone in gene regulation of rat P-glycoproteins mdr1/1b and cytochrome P450 3A1/2[J]. J Pharm Sci,2004,93(10):2488-2496.
108.Wienkers L.C. Factors confounding the successful extrapolation of in vitro CYP3A inhibition information to the in vivo condition[J]. Eur J Pharm Sci,2002,15(3):239-242.
109.Backman J.T., Maenpaa J., Belle D.J., et al. Lack of correlation between in vitro and in vivo studies on the effects of tangeretin and tangerine juice on midazolam hydroxylation[J]. Clin Pharmacol Ther,2000,67(4):382-390.
110.Yamano K., Yamamoto K., Kotaki H., et al. Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats:Implication of concentrative uptake of inhibitors into liver[J]. Drug Metab Dispos.,1999,27(4): 395-402.
111.KOTEGAWA T., LAURIJSSENS B.E., MOLTKE L.L.V., et al. In vitro, pharmacokinetic, and pharmacodynamic interactions of ketoconazole and midazolam in the rat[J]. J Pharmacol Exp Ther,2002,302(3):1228-1237.
112.Thummel K.E., Shen D.D., Podoll T.D., et al. Use of midazolam as a human cytochrome P450 3A probe:Ⅱ. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation[J]. J Pharmacol Exp Ther,1994,271(1):557-566.
113.Galetin A., Ito K., Hallifax D., et al. CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions[J]. J Pharmacol Exp Ther,2005,314(1): 180-190.
114.Rowland M., Tozer T.N.主编,彭彬主译.临床药动学[M].第三版,长沙：湖南科学技术出版社,1995年.
115.Charman, W.N. Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts[J]. J Pharm Sci,2000,89(8):967-978.
116.Khoo S.K., Shackleford D.M., Porter C.J.H., et al. Intestinal lymphatic transport of halofantrine occurs after oral administration of a unit-dose lipid-based formulation to fasted dogs[J]. Pharm Res,2003,20(9):1460-1465.
117.Trevaskis, N.L., Shackleford, D.M., Charman, W.N., et al. Intestinal lymphatic transport enhances the post-prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first-pass metabolism[J]. Pharm. Res.,2009,26(6):1486-1495.
118.Bornemann, L.D., Crews, T., Chen, S.S., et al. Influence of food on midazolam absorption[J]. J Clin Pharmacol,1986,26(1):55-59.
119.Marciani L., Wickham M., Singh G., et al. Enhancement of intragastric acid stability of a fat emulsion meal delays gastric emptying and increases cholecystokinin release and gallbladder contraction[J]. Am J Physiol Gastrointest liver physiol,2007,292(6): G1607-1613.
120.Tachiyashiki K., Imaizumi K. Effects of vegetable oils and C18-unsaturated fatty acids on plasma ethanol levels and gastric emptying in ethanol-administered rats[J]. J Nutr Sci Vitaminol,1993,39(2):163-176.
121.Bornemann L.D., Min B.H, Crews T., et al. Dose dependent pharmacokinetics of midazolam[J]. Eur J Clin Pharmacol,1985,29(1):91-95.
122.Eap C.B., Buclin T., Cucchia G., et al. Oral administration of a low dose of midazolam (75μg) as an in vivo probe for CYP3A activity[J]. Eur J Clin Pharmacol,2004,60(4): 237-246.
123.Lave T., Dupin S., Schmitt C., et al. Integration of in vitro data into allometric scaling to predict hepatic metabolic clearance in man:application to 10 extensively metabolized drugs[J]. J Pharm Sci,1997,86(5):584-590.
124.Lin Y.S., Lockwood G.F., Graham M.A., et al. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration [J]. Pharmacogenetics, 2001,11(9):781-791.
125.Zhu B., Liu Z.Q., Chen X.P., et al. The distribution and gender difference of CYP3A activity in Chinese subject[J]. Br J Clin Pharmacol,2003,55(3):264-269.
126.Benet L.Z., Izumi T., Zhang Y., et al. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery[J]. J Control Release,1999,62(1-2):25-31.
127.Shen D.D., Kunze K.L., Thummel K.E. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction[J]. Adv Drug Deliv Rev,1997,27(2-3):99-127.
128.Tham L.S., Goh B.C., Wang L.Z., et al. Ketoconazole reduced midazolam but not docetaxel pharmacokinetics variability[J]. Clin Pharmacol Ther,2005,79:P23-P23.
1. De Wildt S.N., Keams G.I., Leeder J.S., et al. Cytochrome P450 3A:ontogeny and drug didpodiyion[J]. Clin Pharmacokinet,1999,37(6):485-505.
2. Guengerich F.P. Cytochrome P450 3A:regulation and role in drug metabolism[J]. Annu Rev Pharmacol Toxicol,1999,39:1-17.
3. Lin Y.S., Lockwood G.F., Graham M.A., et al. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration [J]. Pharmacogenetics, 2001,11(9):781-791.
4. Zhu B., Liu Z.Q., Chen X.P., et al. The distribution and gender difference of CYP3A activity in Chinese subject[J]. Br J Clin Pharmacol,2003,55(3):264-269.
5. Ozdemir V., Kalowa W., Tang B.K., et al. Evaluation of the genetic component of variability inCYP3A4 activity:a repeated drug administration method[J]. J Pharmacogenetics,2000,10(5):373-388.
6. Macleod S.L., Nowell S., Massengill J., et al. Cancer therapy and polymorphisms of cytochromesP450[J]. J Clin Chem Lab Med,2000,38(9):883-887.
7.王斌,李德远.细胞色素P450的结构与催化机理[J].有机化学,2009,29(4)：658-662.
8. Poulos T.L., Finzel B.C., Howard A.J. Crystal structure of substrate free Pseudomomonas putida cytochrome P450[J]. Biochem,1986,25(18):5314-5322.
9. Poulos T.L., Finzel B.C., Howard A.J. High-resolution crystal structure of cytochrome P450cam[J]. J Mol Biol,1987,192(3):687-700.
10. Poulos T.L., Finzel B.C., Gunsalus I.C., et al. The 2.6-A crystal structure of Pseudomonas putida cytochrome P450[J]. J Biol Chem,1985,260(30):16122-16130.
11.骆文香,张银娣.药物代谢中的肝细胞色素P450[J].药学进展,1999,23(1)：27-33.
12. Yoshihisa S., Tomoo I., Hitoshil S., et al. Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cycloporin A[J]. J Pharmcol Exp Ther,2003,304(2):610-616.
13. Cotreau M.M., von Moltke L.L., Beinfeld M.C., et al. Methodologies to study the induction of rat hepatic and intestinal cytochrome P450 3A at the mRNA, protein, and catalytic activity level[J]. J Pharmacol Toxicol Methods,2000,43(1):41-54.
14. Wang Z., Gorsi J.C., Hamman M.A., et al. The effect of St John's wort (Hypericum perforatum) on human cytochrome p450 activity[J]. Clin Pharmacol Ther,2001,70 (4): 317-326.
15. Kuo YH, Lin YL, Don MJ, et al. Induction of cytochrome P450 dependent monooxygenase by extracts of the medicinal herb Salvia miltiorrhiza[J]. J Pharm Pharmacol,2006,58 (4):521-527.
16. Paolini M., Pozzetti L., Sapone A., et al. Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases[J]. Life Sci,1998,62(6):571-582.
17.王仁云.贯叶连翘与药物的相互作用[J].中成药,2002,24(11)：875-877.
18. Ogasawara A., Utoh M., Nii K., et al. Effect of oral ketoconazole on oral and intravenous pharmacokinetics of simvastatin and its acid in cynomolgus monkeys[J]. Drug Metab Dispos,2009,37(1):122-128.
19. Krishna G., Moton A., Ma L., et al. Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam:a phase Ⅰ, randomized, open-label, crossover study in healthy volunteers[J]. Clin Ther,2009,31(2):286-298.
20. Goldwater D.R., Dougherty C., Schumacher M., et al. Effect of ketoconazole on the pharmacokinetics of maribavir in healthy adults[J]. Antimicrob Agents Chemother, 2008,52(5):1794-1798.
21. Ridtitid W., Ratsamemonthon K., Mahatthanatrakul W., et al. Pharmacokinetic interaction between ketoconazole and praziquantel in healthy volunteers[J]. J Clin Pharm Ther,2007,32(6):585-593.
22. Ohno Y., Hisaka A., Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs[J]. Clin Pharmacokinet,2007,46(8):681-696.
23. Shimada T, Yamazaki H., Mimura M., et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals:studies with liver microsomes of 30 Japanese and 30 Caucasians[J]. J Pharmcol Exp Ther,1994,270(1):414-423.
24. Zhang Q.Y., Dunbar D., Ostrowska A., et al. Characterization of human small intestinal cytochromes P-450[J]. Drug Metab Dispos,1999,27 (7):804-809.
25. Hsing S., Gatmaitan Z., Arias I.M. The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa[J]. Gastroenterology,1992,102(3): 879-885.
26. Terao T., Hisanaga E, Sai Y., et al. Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier[J]. J Pharm Pharmacol,1996,48(10): 1083-1089.
27. Cummins C.L., Jacobsen W., Benet L.Z. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4[J]. J Pharmcol Exp Ther,2002,300(3):1036-1045.
28. Okamoto J., Fukunami M., Kioka H. Frequent premature ventricular contractions induced by itraconazole[J]. Circ J,2007,71(8):1323-1325.
29. Skov M., Main K.M., Sillesen I.B., et al. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide[J]. Eur Respir J,2002, 20(1):127-133.
30. Reif S., Kingreen D., Kloft C., et al. Bioequivalence investigation of high-dose etoposide and etoposide phosphate in lymphoma patients [J]. Cancer Chemother Pharmacol,2001,48(2):134-140.
31. Choi C.H., Kim J.H., Kim S.H. Reversal of P-glycoprotein-mediated MDR by 5,7,3',4',5'-pentamethoxyflavone and SAR[J]. Biochem Biophy Res commomm,2004, 320(3):672-679.
32. Mountfield R.J., Senepin S., Schleimerm M., et al. Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450[J]. Int J Pharm,2000,211(1-2): 89-92.
33. Bravo-Gonzalez R.C., Huwyler J., Boess F., et al. In vito investigation on the impact of the suface-active excipients Cremophor EL、Tween 80 and Solutol HS 15 on the metabolism of midazolam[J]. Biopharm Drug Dispos,2004,25(1):37-49.
34. Bogman K, Erne-Brand F, Alsenz J, et al. The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins[J]. J Pharm Sci,2003,92(6): 1250-1261.
35. Ren XH, Si LQ, Cao L., et al. Effect of polyoxyl ether analogous surfactans on the activity of cytochromes 3A in rats in vivo[J]. Acta Pharm Sin (药学学报),2008,43(5): 529-534.
36. Ren X.H., Mao X.L., Si L.Q., et al. Pharmaceutical excipients inhibit cytochrome P450 activity in cell free systems and after systemic administration[J]. Eur J Pharm Biopharm, 2008,70(1):279-288.
37. Da-Silva M.E.F., Meirelles N.C. Interaction of non-ionic surfactants with hepatic CYP in prochilodus scrofa[J]. Toxicol In Vitro,2004,18(6):859-867.
38. Ren X.H., Mao X.L., Cao L., et al. Nonionic surfactants are strong inhibitors of cytochrome P450 3A biotransformation activity in vitro and in vivo[J]. Eur J Pharm Sci, 2009,36(4-5):401-411.
39. Bittner B., Bravo-Gonzalez R.C., Walter I., et al. Impact of Solutol HS 15 on the pharmacokinetic behaviour of colchicines upon intravenous administration to male wistar rats[J]. Biopharm Drug Dispos,2003,24(4):173-181.
40. Bittner B., Bravo-Gonzalez R.C., Isel H., et al. Impact of Solutol HS 15 on the pharmacokinetic behavior of midazolam upon intravenous administration to male wistar rats[J]. Eur J Pharm Biopharm,2003,56(1):143-146.
41. Lave T., Dupin S., Schmitt C., et al. Integration of in vitro data into allometric scaling to predict hepatic metabolic clearance in man:application of 10 extensively metabolized drugs[J]. J Pharm Sci,1997,86(5):584-590.
42. Aranzazu-Partearroyo M., Ostolaza H., Goni F.M., et al. Surfactant-induced cell toxicity and cell lysis. A study using B16 melanoma cells[J]. Biochem Pharmacol,1990, 40(6):1323-1328.
43.任秀华,斯陆勤,曹磊等.单次不同剂量PEG 400对大鼠体内细胞色素P450 3A活 性的影响[J].中国药学杂志,2009,44(2)：345-348.
44.任秀华,斯陆勤,曹磊等.多次不同剂量PEG 400对大鼠体内细胞色素P450 3A活性的影响[J].中国医院药学杂志,2008,28(22)：1912-1916.
45. Cotreau-Bibbo M.M., Von-Moltke L.L., Greenblatt D.J., et al. Influence of polyethylene glycol and acetone on the in vitro biotransformation of tamoxifen and alprazolam by human liver microsomes[J]. J Pharm Sci,1996,85(11):1180-1185.
46. Iwase M., Kurate R., Ehana R., et al. Evaluation of the effects of hydrophilic organic solvents on CYP3A-mediated drug-drug interaction in vitro[J]. Hum Exp Toxicol,2006, 25(12):715-721.
47. Chauret N., Gauthier A., Nicoll-Griffith D.A., et al. Effect of common organic solvents on in vitro cytochrome P450-mediated metabolic activities in human liver microsomes[J]. Drug Metab Dispos,1998,26(1):1-4.
48. Hickman D., Wang J.P., Wang Y., et al. Evaluation of the selectivity of in vitro probes and suitability of organic solvents for the measurement of human cytochrome P450 monooxygenase activities[J]. Drug Metab Dispos,1998,26(3):207-215.
49. Huang J.G., Si L.Q., Jiang L.L., et al. Effect of pluronic F68 block copolymer on P-glycoprotein transport and CYP3A4 metabolism[J]. Int J Pharm,2008,356(1-2): 351-353.
50.赵冬梅,李燕.药物代谢研究在新药开发中的作用[J].药学学报,2000,35(2)：156-160.
51. Riordan S., Williams R. Bioartificial livers support:developments in hepatoeyte culture and bioreactor design[J]. Br Med Bull,1997,53(4):730-734.
52. Wrighton S.A., Ring B. J., VandenBranden M. The use of in vitro metabolism techniques in the planning and interpretation of drug safety studies[J]. Toxicol. Pathol.,1995,23(2): 199-208.
53. Wienkers L.C. Factors confounding the successful extrapolation of in vitro CYP3A inhibition information to the in vivo condition[J]. Eur J Pharm Sci,2002,15(3):239-242.
54. Backman J.T., Maenpaa J., Belle D.J., et al. Lack of correlation between in vitro and in vivo studies on the effects of tangeretin and tangerine juice on midazolam hydroxylation[J]. Clin Pharmacol Ther,2000,67(4):382-390.
55. Patki K.C., Von Moltke L.L., Greenblatt D.J. In vitro metabolism of midazolam, triazolam, Nifedipine, and testosterone by human liver microsomes and recombinant cyochromes P450:role of CYP3A4 and CYP3A5[J]. Drug Metab Dispos,2003,31(7): 938-945.
2. Zhang Q.Y., Dunbar D., Ostrowska A., et al.Characterization of human small intestinal cytochromes P-450[J]. Drug Metab Dispos,1999,27 (7):804-809.
3. Hsing S., Gatmaitan Z., Arias I.M. The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa[J]. Gastroenterology,1992, 102(3):879-885.
4. Terao T., Hisanaga E., Sai Y., et al. Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier[J]. J Pharm Pharmacol,1996,48(10):1083-1089.
5. Cummins C.L., Jacobsen W., Benet L.Z. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4[J]. J Pharmcol Exp Ther,2002, 300(3):1036-1045.
6. Ogasawara A., Utoh M., Nii K., et al. Effect of oral ketoconazole on oral and intravenous pharmacokinetics of simvastatin and its acid in cynomolgus monkeys[J]. Drug Metab Dispos,2009,37(1):122-128.
7. Krishna G., Moton A., Ma L., et al. Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam:a phase Ⅰ, randomized, open-label, crossover study in healthy volunteers[J]. Clin Ther,2009,31(2):286-98.
8. Goldwater D.R., Dougherty C., Schumacher M., et al. Effect of ketoconazole on the pharmacokinetics of maribavir in healthy adults[J]. Antimicrob Agents Chemother, 2008,52(5):1794-1798.
9. Ridtitid W., Ratsamemonthon K., Mahatthanatrakul W., et al. Pharmacokinetic interaction between ketoconazole and praziquantel in healthy volunteers[J]. J Clin Pharm Ther,2007,32(6):585-593.
10. Ohno Y, Hisaka A., Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs[J]. Clin Pharmacokinet,2007,46(8):681-696.
11. Okamoto J., Fukunami M., Kioka H. Frequent premature ventricular contractions induced by itraconazole[J]. Circ J,2007,71(8):1323-1325.
12. Skov M., Main K.M., Sillesen I.B., et al. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide[J]. Eur Respir J, 2002,20(1):127-133.
13. Reif S., Kingreen D., Kloft C., et al. Bioequivalence investigation of high-dose etoposide and etoposide phosphate in lymphoma patients[J]. Cancer Chemother Pharmacol,2001,48(2):134-140.
14. Choi C.H., Kim J.H., Kim S.H. Reversal of P-glycoprotein-mediated MDR by 5,7,3',4',5'-pentamethoxyflavone and SAR[J]. Biochem Biophy Res commomm,2004, 320(3):672-679.
15. Bravo Gonzalez R.C., Huwyler J., Boess F., et al. In vitro investigation on the impact of the surface-active excipients Cremophor EL, Tween 80 and Solutol HS 15 on the metabolism of midazolam[J]. Biopharm Drug Dispos,2004,25(1):37-49.
16. Lipinski C.J. Poor aqueous solubility-an industry wide problem in drug discovery[J]. Am Pharm Rev,2002,5(1):82-85.
17. Kim R.B., Wandel C., Leake B., et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein[J]. Pharm Res,1999,16(3):408414.
18. Ren X.H., Si L.Q., Li G., et al. Pharmaceutical Excipients Inhibit Cytochrome P450 Activity in Cell Free Systems and After Systemic Administration[J]. Eur J Pharm Biopharm,2008,70(1):279-288.
19. Gursoy R.N., Benita S. Self-emulsifying drug delivery systems(SEDDS) for improved oral delivery of lipophilic drug[J]. Biomed Pharmacother,2004,58(3):173-182.
20. Bravo-Gonzalez R.C., Huwyler J., Walter I., et al. Improved oral bioavailability of cyclosporine A in male wistar rats. comparison of a solutol HS 15 containing
self-dispersing formulation and a microsuspension[J]. Int J Pharm,2002, 245(1-2):143-151.
21.平其能,胡一桥,周建平.现代药剂学[M].北京：中国医药工业出版社,2001年.
22. Ranaldi G., Consalvo R., Sambuy Y., et al. Permeability characteristics of parental and clonal human intestinal Caco-2 cell lines differentiated in serum-supplemented and serum-free media[J]. Toxicology in Vitro,2003,17(5):761-767.
23. Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man-fact or myth[J]. Pharm Res,1997,14(6):763-766.
24.郭勇,郑穗平.酶学[M].广州：华南理工大学出版社,2000年.
25. Cotreau M.M., von Moltke L.L., Beinfeld M.C., et al. Methodologies to study the induction of rat hepatic and intestinal cytochrome P450 3A at the mRNA, protein and catalytic activity level[J]. J Pharmacol Toxicol Methods,2000,43(1):41-54.
26. Bradford M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding[J]. Anal Biochem, 1976,2:248-254.
27.李高,陈鹰,王瑞华.长春西汀自微乳化给药系统的研究[J].中国药学杂志,2006,41(23)：1795-1799.
28. Kim R.B., Wandel C., Leake B., et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein[J]. Pharm Res,1999,16(3):408-414.
29. Benet L.Z., Cummins C.L. The drug efflux-metabolism alliance:biochemical aspect[J]. Adv Drug Deliv Rev,2001,50(sup 1):S3-S11.
30. Polli J.W., Wring S.A., Humphreys J.E., et al. Rational use of in vitro P-glycoprotein assays in drug discovery[J]. J Pharmacol Exp Ther,2001,299(2):620-628.
31. Wandel C., Bocker R., Bohrer H., et al. Midazolam is metabolized by at least three different cytochrome P450 enzymes[J]. Br J Anaesth,1994,75(3):658-661.
32. Fumico H., Teruo M., Tatsuya K., et al. Dose-dependent intestinal and hepatic first-pass metabolism of midazolam, a cytochrome P450 3A substrate with differently modulated enzyme activity in rats[J]. J. Pharm. Pharmacol.,1999,51(1):67-72.
33. Eeckhoudt S.L., Horsmans Y., Verbeeck R.K. Differential induction of midazolam metabolism in the small intestine and liver by oral and intravenous dexamethasone pretreatment in rat[J]. Xenobiotica,2001,32(11):975-984.
34. Ribeiro V., Lechner M.C. Cloning and characterization of a novel CYP3A1 allelic variant:analysis of CYP3A1 and CYP3A2 sex-hormone-dependent expression reveals that the CYP3A2 gene is regulated by testosterone[J]. Arch Biochem Biophys,1992, 293(1):147-152.
35. Chen M.L. Lipid excipients and delivery systems for pharmaceutical development:A regulatory perspective[J]. Adv Drug Deliv Reviews,2008,60:768-777.
36. Jin M., Shimada T., Yokogawa K., et al. Cremophor EL releases cyclosporine A adsorbed on blood cells and blood vessels, and increases apparent plasma concentration of cyclosporine A[J]. Int J Pharm,2005,293(1-2):137-144.
37. Scott Obach R., Reed-hagen A.E.. Measurement of michaelis constantants for cytochrome P450-mediated bioransformation reactions using a substrate depletion approach[J]. Drug Metab. Dispos.,2002,30(7):831-837.
38. Mountfield R.J., Senepin S., Schleimer M., et al. Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450[J]. Int J Pharm,2000, 211(1-2):89-92.
39. Gershanik T., Haltner E., Lehr C.M., et al. Charge-dependent interaction of self-emulsifying oil formulations with Caco-2 cell monolayers:binding, effects on barrier function and cytotoxicity[J]. Int J Pharm,2000,211(1-2):29-36
40. Tarr B.D., Yalkowsky S.H. Enhanced intestinal absorption of cyclosporine in rats through the reduction of emulsion droplet size[J]. Pharm Res,1989,6(1):40-43
41. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption:physical and biopharmaceutical aspects[J]. Pharm Res,1995,12(11): 1561-1572.
42. Okonogi S., Oguchi T., Yonemochi E., et al. Improved dissolution of ofloxacin via solid dispersion[J]. Int J Pharm,1997,156(2):175-180.
43. Yoo S.D., Lee S.H., Kang E., et al. Bioavailability of itraconazole in rats and rabbits after administration of tablets containing solid dispersion particles[J]. Drug Dev Ind Pharm,2000,26(1):27-34.
44. Shui M., Andrew J., Christopher J. Formulation design and bioavailability assessment of lipidic self-emulsifying formulation of halofantrine[J]. Int J Pharm,1998,167(1-2): 155-164.
45.涂秋榕,朱颖,朱家璧.尼莫地平自微乳化液的处方研究[J].中国药学杂志,2005,40(3)：43-46.
46.吴伟崔光华.星点设计—效应面优化法及其在药学中的应用[J].国外医学药学分册,2000,27(5)：292-299.
47.陆彬吴伟.中心多点等距设计法优化醋酸地塞米松聚丙交酯微球的制备工艺[J].药学学报,1999,34(5)：387-391.
48.郑俊民主译药用辅料手册[M].第四版,北京：化学工业出版社,2005年.
49. Gershanik T., Benzeno S., Benita S., et al. Interaction of a self-emulsifying lipid drug delivery system with the everted rat intestinal mucosa as a function of droplet size and surface charge[J]. Pharm. Res.,1998,15(6):863-869.
50. Gershanik T., Benita S. Positively charged self-emulsifying oil formulation for improving oral bioavailability of progesterone[J]. Pharm. Dev. Technol.,1996,1(2): 147-157.
51. Holm R., Porter C.J.H., Edwards G.A., et al. Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery containing structured triglycerides[J]. Eur. J. Pharm. Sci.,2003,20(2):90-97.
52.张学农,唐丽华,阎雪莹,等.紫杉醇自乳化微乳的制备及其在大鼠体内的药动学[J].中国新药与临床杂志,2005,24(4)：294-298.
53.凌桂霞,孙进,殷静,等.桂利嗪自微乳化软胶囊的制备和溶出度的考察[J].中国药学杂志,2005,40(19)：1452-1454.
54. Shah N.H., Canajal M.T., Patel C.I., et al. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs[J]. Int J Pharm,1994,106(1):15-23.
55. Kang B.K., Lee J.S., Chon S.K., et al. Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs[J]. Int J Pharm,2004,274(1-2):65-73.
56. Wakerly M.C.P., Pouton C.W., Meakin B.J. Evaluation of the self-emulsifying performance of a non-ionic surfactant-vegetable oil mixture[J]. J Pharm Pharmacol, 1987,39(1):6P-6P.
57. Craig D.Q.M., Barker S.A., Banning D., et al. An investigation into the mechanisms of self -emulsification using particle size analysis and low frequency dielectric spectroscopy[J]. Int J Pharm,1995,114(1):103-110.
58. Kommuru T.R., Gurley B., Khan M.A., et al. Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10:formulation development and bioavailability assessment[J]. Int J Pharm,2001,212(1):233-246.
59. Pouton C.W. Formulation of self-emulsifying drug delivery systems [J]. Adv Drug Deliv Reviews,1997,25(1):47-58.
60. Giannakou SA., Dallas PP., Rekkas DM., et al. In vitro evaluation of nimodipine permeation through human epidermis using response surface methodology[J]. Int J Pharm,2002,241(1):27-34.
61. Kagkadis KA., Rekkas DM., Dallas PP., et al. A freeze-dried injection form of flurbiprofen:development and optimization using response surface methodology[J]. Int J Pharm,1998,161(1):87-94.
62. Colin W.P. Self-emulsifying drug delivery systems:assessment of the efficiency of emulsification[J]. Int J Pharm,1985,27(2-3):335-348.
63. Bachynsky M.O., Shah N.H., Patel C.I., et al. Factors affecting the efficiency of a self-emulsifying oral delivery system[J]. Drug Deve Ind Pharm.,1997,23(8):809-816.
64. Gershanik T., Benzeno S., Beniton S. Interaction of self-emulsifying lipid drug delivery system with the everted rat intestinal macosa as a fuction of droplet size and
surface charge[J]. Pharm Res,1998,15(6):863-869.
65. Pouton C.W. Lipid formulation for oral administration of drug:non-emulsifying, self-emulsifying and "self-microemulsifying" drug delivery systems[J]. Eur J Pharm Sci,2000, 11(suppl 2):S93-S98.
66. Trotta M.A. Affluence of phase transformation on indomethacine release of microemul sions[J]. J Control Release,1999,60(2-3):399-405.
67.王懿睿,杜光.伊曲康唑自微乳化释药系统体外释放的评价方法[J].中国医院药学杂志,2008,28(11)：877-880.
68.毕殿洲.药剂学(第三版)[M].北京：人民卫生出版社,1999年.
69. Shah N.H., Carvajal M.T., Patel C.I., et al. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drug[J]. Int J Pharm,1994,106:15-23.
70. Perlman, M.E., Murdande, S.B., Gumkowski, M.J., et al. Development of a self-emulsifying formulation that reduces the food effect for tocetrapib[J]. Int J Pharm, 2008,351(1-2):15-22.
71. Cuine J.F., Mcevoy C.L., Charman W.N., et al. Evaluation of the impact of surfactant digestion on the bioavailability of danazol after oral administration of lipidic self-emulsifying formulations to dogs[J]. J Pharm Sci,2008,97(2):995-1011.
72.张莉,夏运岳.用电子表格Excel计算药物溶出度Weibull分布参数[J].药学进展,2002,26(1)：48-50.
73. Chen Y., Li G., Wu X.G., et al. Self-microemulsifying drug delivery system(SMEDDS) of vinpocetine:formulation development and in vivo assessment[J]. Biol Pharm Bull, 2008,31(1):118-125.
74. Wu W., Wang Y., Que L. Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system[J]. Eur J Pharm Biopharm,2006,63(3): 288-294.
75. Zhang P., Liu Y., Feng N.P., et al. Preparation and evaluation of self-microemulsifying drug delivery system of oridonin[J]. Int J Pharm,2008,355(1-2):269-276.
76. Nishimura, T., Amano, N., Kubo, Y., et al. Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey[J]. Drug Metab Dispos,2007,35(8):1275-1284.
77. Paine, M.F., Shen, D.D., Kunze, K.L., et al. First-pass metabolism of midazolam by the human intestine[J]. Clin Pharmacol Ther,1996,60(1):14-24.
78.赵冬梅,李燕.药物代谢研究在新药开发中的作用[J].药学学报,2000,35(2)：156-160.
79. Riordan S., Williams R. Bioartificial livers support:developments in hepatoeyte culture and bioreactor design[J]. Br Med Bull,1997,53(4):730-734.
80. Seglen PO. Preparation of isolated rat liver cells[J]. Methods Cell Biol,1976,13: 29-83.
81. Kienhuis AS et al. A sandwich-cultured rat hepatocyte system with increased metabolic competence evaluated by gene expression profiling[J]. Toxicol in Vitro,2007,21(5): 892-901.
82.薛俊峰,李桦,阮金秀,等.氮烯乙茶在成年大鼠肝细胞中的生物转化[J].药学学报,1999,34(10)：739-743
83. Lu C., Li P., Gallegos R., et al. Comparison of intrinsic clearance in liver microsomes and hepatocytes from rats and humans:evaluation of free fraction and uptake in hepatocytes[J]. Drug Metab Dispos 2006,34(9):1600-1605.
84. Wang K., Shindoh H., Tomoaki I., et al. Advantages of in vitro cytotoxicity testing by using primary rat hepatocytes in comparison with established cell lines[J]. J Toxicol Sci,2002,27(3):229-237.
85. Albert P., Human hepatocytes:Isolation,cryopreservation and applications in drug development[J]. Chem Biol Interact,2007,168(1):16-29.
86. Quattrochi L.C., Guzelian P.S. CYP3A regulation:from pharmacology to nuclear receptors[J]. Drug Metab Dispos,2001,29(5):615-622.
87. Xie W., Evans R.M. Orphan nuclear receptors:the exotics of xenobiotics[J]. J Biol Chem,2001,276(41):37739-37742.
88. Da-Silva M.E.F., Meirelles N.C. Interaction of non-ionic surfactants with hepatic CYP in prochilodus scrofa[J]. Toxicol in Vitro,2004,18(6):859-867.
89. Yun C.H., Song M., Ahn T., et al. Conformational change of cytochrome P 450 1A2 induced by sodium chloride[J]. J Biol Chem,1996,271(49):31312-31316.
90. Halpert JR. Structural basis of selective cytochrome P450 inhibition [J]. Annu Rev Pharmacol Toxicol,1995,35:29-53.
91. Aranzazu-Partearroyo M., Ostolaza H., Goni F.M., et al. Surfactant-induced cell toxicity and cell lysis. A study using B16 melanoma cells[J]. Biochem Pharmacol, 1990,40(6):1323-1328.
92. Kamm W., Jonczyk A., Jung T., et al. Evaluation of absorption enhancement for a potent cyclopeptidic αvβ3-anatgonist in a human intestinal cell line (Caco-2)[J]. Eur J Pharm Sci,2000,10(3):205-214.
93. Guengerich F.P., Martin M.V., Beaune P.H., et al. Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism [J]. J Biol Chem, 1986,261(11):5051-5060.
94. Sumida A., Kinoshita K., Fukuda T., et al. Relationship between mRNA levels quantified by reverse transcription-competitive PCR and metabolic activity of CYP3A4 and CYP2E1 in human liver[J]. Biochem Biophys Res Commun,1999, 262(2):499-503.
95. Cotreau M.M., von Moltke L.L., Beinfeld M.C., et al. Methodologies to study the induction of rat hepatic and intestinal cytochrome P450 3A at the mRNA, protein, and catalytic activity level[J]. J Pharmacol Toxicol Methods,2000,43(1):41-54.
96. Thummel KE, O'Shea D, Paine MF, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism[J]. Clin Pharmacol Ther,1996,59(5):491-502.
97. Paine MF, Shen DD, Kunze KL, et al. First pass metabolism of midazolam by the human intestine[J]. Clin Pharmacol Ther,1996,60(1):14-24.
98. Lim Y.P., Kuo S.C., Lai M.L., et al. Inhibition of CYP3A4 expression by ketoconazole is mediated by the disruption of pregnane X receptor, steroid receptor coactivator-1, and hepatocyte nuclear factor 4alpha interaction[1]. Pharmacogenet Genomics,2009,19(1): 11-24.
99. Fujita T., Yasuda S., Kamata Y., et al. Contribution of down-regulation of intestinal and hepatic cytochrome P450 3A to increased absorption of cyclosporine A in a rat nephrosis model[J]. J Pharmacol Exp Ther,2008,327(2):592-599.
100.黄林清,杨志勇.肝细胞色素P450与药物代谢的研究进展[J].中国药房,2001,12(6)：372-374.
101.Andersson T., Koivusaari U., Influence of environmental temperature on the induction of xenobiotic metabolism by β-naphoflavone in rainbow trout, Saino garidneri[J]. Toxicol Appl Phamacol,1985,80(1):45-50
102.金念祖,陆晓和.食物、细胞色素P450酶与药物代谢[J].上海环境科学,2001,20(2)：87-91.
103.骆文香,张银娣.药物代谢中的肝细胞色素P450[J].药学进展,1999,23(1)：27-33.
104.Bookout A.L., Jeong Y., Downes M., et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network[J]. Cell,2006,126(4):789-799.
105.Chawla A., Repa J J., Evans R.M., et al. Nuclear receptors and lipid physiology:opening the X-files[J]. Science,2001,294(5548):1866-1870.
106.Lee C.H., Plutzky J. Liver X receptor activation and high-density lipoprotein biology:a reversal of fortune[J]. Circulation,2006,113(1):5-8.
107.Mei Q., Richards K., Strong-Basalyga K., et al. Using real-time quantitative TaqMan RT-PCR to evaluate the role of dexamethasone in gene regulation of rat P-glycoproteins mdr1/1b and cytochrome P450 3A1/2[J]. J Pharm Sci,2004,93(10):2488-2496.
108.Wienkers L.C. Factors confounding the successful extrapolation of in vitro CYP3A inhibition information to the in vivo condition[J]. Eur J Pharm Sci,2002,15(3):239-242.
109.Backman J.T., Maenpaa J., Belle D.J., et al. Lack of correlation between in vitro and in vivo studies on the effects of tangeretin and tangerine juice on midazolam hydroxylation[J]. Clin Pharmacol Ther,2000,67(4):382-390.
110.Yamano K., Yamamoto K., Kotaki H., et al. Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats:Implication of concentrative uptake of inhibitors into liver[J]. Drug Metab Dispos.,1999,27(4): 395-402.
111.KOTEGAWA T., LAURIJSSENS B.E., MOLTKE L.L.V., et al. In vitro, pharmacokinetic, and pharmacodynamic interactions of ketoconazole and midazolam in the rat[J]. J Pharmacol Exp Ther,2002,302(3):1228-1237.
112.Thummel K.E., Shen D.D., Podoll T.D., et al. Use of midazolam as a human cytochrome P450 3A probe:Ⅱ. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation[J]. J Pharmacol Exp Ther,1994,271(1):557-566.
113.Galetin A., Ito K., Hallifax D., et al. CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions[J]. J Pharmacol Exp Ther,2005,314(1): 180-190.
114.Rowland M., Tozer T.N.主编,彭彬主译.临床药动学[M].第三版,长沙：湖南科学技术出版社,1995年.
115.Charman, W.N. Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts[J]. J Pharm Sci,2000,89(8):967-978.
116.Khoo S.K., Shackleford D.M., Porter C.J.H., et al. Intestinal lymphatic transport of halofantrine occurs after oral administration of a unit-dose lipid-based formulation to fasted dogs[J]. Pharm Res,2003,20(9):1460-1465.
117.Trevaskis, N.L., Shackleford, D.M., Charman, W.N., et al. Intestinal lymphatic transport enhances the post-prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first-pass metabolism[J]. Pharm. Res.,2009,26(6):1486-1495.
118.Bornemann, L.D., Crews, T., Chen, S.S., et al. Influence of food on midazolam absorption[J]. J Clin Pharmacol,1986,26(1):55-59.
119.Marciani L., Wickham M., Singh G., et al. Enhancement of intragastric acid stability of a fat emulsion meal delays gastric emptying and increases cholecystokinin release and gallbladder contraction[J]. Am J Physiol Gastrointest liver physiol,2007,292(6): G1607-1613.
120.Tachiyashiki K., Imaizumi K. Effects of vegetable oils and C18-unsaturated fatty acids on plasma ethanol levels and gastric emptying in ethanol-administered rats[J]. J Nutr Sci Vitaminol,1993,39(2):163-176.
121.Bornemann L.D., Min B.H, Crews T., et al. Dose dependent pharmacokinetics of midazolam[J]. Eur J Clin Pharmacol,1985,29(1):91-95.
122.Eap C.B., Buclin T., Cucchia G., et al. Oral administration of a low dose of midazolam (75μg) as an in vivo probe for CYP3A activity[J]. Eur J Clin Pharmacol,2004,60(4): 237-246.
123.Lave T., Dupin S., Schmitt C., et al. Integration of in vitro data into allometric scaling to predict hepatic metabolic clearance in man:application to 10 extensively metabolized drugs[J]. J Pharm Sci,1997,86(5):584-590.
124.Lin Y.S., Lockwood G.F., Graham M.A., et al. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration [J]. Pharmacogenetics, 2001,11(9):781-791.
125.Zhu B., Liu Z.Q., Chen X.P., et al. The distribution and gender difference of CYP3A activity in Chinese subject[J]. Br J Clin Pharmacol,2003,55(3):264-269.
126.Benet L.Z., Izumi T., Zhang Y., et al. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery[J]. J Control Release,1999,62(1-2):25-31.
127.Shen D.D., Kunze K.L., Thummel K.E. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction[J]. Adv Drug Deliv Rev,1997,27(2-3):99-127.
128.Tham L.S., Goh B.C., Wang L.Z., et al. Ketoconazole reduced midazolam but not docetaxel pharmacokinetics variability[J]. Clin Pharmacol Ther,2005,79:P23-P23.
1. De Wildt S.N., Keams G.I., Leeder J.S., et al. Cytochrome P450 3A:ontogeny and drug didpodiyion[J]. Clin Pharmacokinet,1999,37(6):485-505.
2. Guengerich F.P. Cytochrome P450 3A:regulation and role in drug metabolism[J]. Annu Rev Pharmacol Toxicol,1999,39:1-17.
3. Lin Y.S., Lockwood G.F., Graham M.A., et al. In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration [J]. Pharmacogenetics, 2001,11(9):781-791.
4. Zhu B., Liu Z.Q., Chen X.P., et al. The distribution and gender difference of CYP3A activity in Chinese subject[J]. Br J Clin Pharmacol,2003,55(3):264-269.
5. Ozdemir V., Kalowa W., Tang B.K., et al. Evaluation of the genetic component of variability inCYP3A4 activity:a repeated drug administration method[J]. J Pharmacogenetics,2000,10(5):373-388.
6. Macleod S.L., Nowell S., Massengill J., et al. Cancer therapy and polymorphisms of cytochromesP450[J]. J Clin Chem Lab Med,2000,38(9):883-887.
7.王斌,李德远.细胞色素P450的结构与催化机理[J].有机化学,2009,29(4)：658-662.
8. Poulos T.L., Finzel B.C., Howard A.J. Crystal structure of substrate free Pseudomomonas putida cytochrome P450[J]. Biochem,1986,25(18):5314-5322.
9. Poulos T.L., Finzel B.C., Howard A.J. High-resolution crystal structure of cytochrome P450cam[J]. J Mol Biol,1987,192(3):687-700.
10. Poulos T.L., Finzel B.C., Gunsalus I.C., et al. The 2.6-A crystal structure of Pseudomonas putida cytochrome P450[J]. J Biol Chem,1985,260(30):16122-16130.
11.骆文香,张银娣.药物代谢中的肝细胞色素P450[J].药学进展,1999,23(1)：27-33.
12. Yoshihisa S., Tomoo I., Hitoshil S., et al. Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cycloporin A[J]. J Pharmcol Exp Ther,2003,304(2):610-616.
13. Cotreau M.M., von Moltke L.L., Beinfeld M.C., et al. Methodologies to study the induction of rat hepatic and intestinal cytochrome P450 3A at the mRNA, protein, and catalytic activity level[J]. J Pharmacol Toxicol Methods,2000,43(1):41-54.
14. Wang Z., Gorsi J.C., Hamman M.A., et al. The effect of St John's wort (Hypericum perforatum) on human cytochrome p450 activity[J]. Clin Pharmacol Ther,2001,70 (4): 317-326.
15. Kuo YH, Lin YL, Don MJ, et al. Induction of cytochrome P450 dependent monooxygenase by extracts of the medicinal herb Salvia miltiorrhiza[J]. J Pharm Pharmacol,2006,58 (4):521-527.
16. Paolini M., Pozzetti L., Sapone A., et al. Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases[J]. Life Sci,1998,62(6):571-582.
17.王仁云.贯叶连翘与药物的相互作用[J].中成药,2002,24(11)：875-877.
18. Ogasawara A., Utoh M., Nii K., et al. Effect of oral ketoconazole on oral and intravenous pharmacokinetics of simvastatin and its acid in cynomolgus monkeys[J]. Drug Metab Dispos,2009,37(1):122-128.
19. Krishna G., Moton A., Ma L., et al. Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam:a phase Ⅰ, randomized, open-label, crossover study in healthy volunteers[J]. Clin Ther,2009,31(2):286-298.
20. Goldwater D.R., Dougherty C., Schumacher M., et al. Effect of ketoconazole on the pharmacokinetics of maribavir in healthy adults[J]. Antimicrob Agents Chemother, 2008,52(5):1794-1798.
21. Ridtitid W., Ratsamemonthon K., Mahatthanatrakul W., et al. Pharmacokinetic interaction between ketoconazole and praziquantel in healthy volunteers[J]. J Clin Pharm Ther,2007,32(6):585-593.
22. Ohno Y., Hisaka A., Suzuki H. General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs[J]. Clin Pharmacokinet,2007,46(8):681-696.
23. Shimada T, Yamazaki H., Mimura M., et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals:studies with liver microsomes of 30 Japanese and 30 Caucasians[J]. J Pharmcol Exp Ther,1994,270(1):414-423.
24. Zhang Q.Y., Dunbar D., Ostrowska A., et al. Characterization of human small intestinal cytochromes P-450[J]. Drug Metab Dispos,1999,27 (7):804-809.
25. Hsing S., Gatmaitan Z., Arias I.M. The function of Gp170, the multidrug-resistance gene product, in the brush border of rat intestinal mucosa[J]. Gastroenterology,1992,102(3): 879-885.
26. Terao T., Hisanaga E, Sai Y., et al. Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier[J]. J Pharm Pharmacol,1996,48(10): 1083-1089.
27. Cummins C.L., Jacobsen W., Benet L.Z. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4[J]. J Pharmcol Exp Ther,2002,300(3):1036-1045.
28. Okamoto J., Fukunami M., Kioka H. Frequent premature ventricular contractions induced by itraconazole[J]. Circ J,2007,71(8):1323-1325.
29. Skov M., Main K.M., Sillesen I.B., et al. Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide[J]. Eur Respir J,2002, 20(1):127-133.
30. Reif S., Kingreen D., Kloft C., et al. Bioequivalence investigation of high-dose etoposide and etoposide phosphate in lymphoma patients [J]. Cancer Chemother Pharmacol,2001,48(2):134-140.
31. Choi C.H., Kim J.H., Kim S.H. Reversal of P-glycoprotein-mediated MDR by 5,7,3',4',5'-pentamethoxyflavone and SAR[J]. Biochem Biophy Res commomm,2004, 320(3):672-679.
32. Mountfield R.J., Senepin S., Schleimerm M., et al. Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450[J]. Int J Pharm,2000,211(1-2): 89-92.
33. Bravo-Gonzalez R.C., Huwyler J., Boess F., et al. In vito investigation on the impact of the suface-active excipients Cremophor EL、Tween 80 and Solutol HS 15 on the metabolism of midazolam[J]. Biopharm Drug Dispos,2004,25(1):37-49.
34. Bogman K, Erne-Brand F, Alsenz J, et al. The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins[J]. J Pharm Sci,2003,92(6): 1250-1261.
35. Ren XH, Si LQ, Cao L., et al. Effect of polyoxyl ether analogous surfactans on the activity of cytochromes 3A in rats in vivo[J]. Acta Pharm Sin (药学学报),2008,43(5): 529-534.
36. Ren X.H., Mao X.L., Si L.Q., et al. Pharmaceutical excipients inhibit cytochrome P450 activity in cell free systems and after systemic administration[J]. Eur J Pharm Biopharm, 2008,70(1):279-288.
37. Da-Silva M.E.F., Meirelles N.C. Interaction of non-ionic surfactants with hepatic CYP in prochilodus scrofa[J]. Toxicol In Vitro,2004,18(6):859-867.
38. Ren X.H., Mao X.L., Cao L., et al. Nonionic surfactants are strong inhibitors of cytochrome P450 3A biotransformation activity in vitro and in vivo[J]. Eur J Pharm Sci, 2009,36(4-5):401-411.
39. Bittner B., Bravo-Gonzalez R.C., Walter I., et al. Impact of Solutol HS 15 on the pharmacokinetic behaviour of colchicines upon intravenous administration to male wistar rats[J]. Biopharm Drug Dispos,2003,24(4):173-181.
40. Bittner B., Bravo-Gonzalez R.C., Isel H., et al. Impact of Solutol HS 15 on the pharmacokinetic behavior of midazolam upon intravenous administration to male wistar rats[J]. Eur J Pharm Biopharm,2003,56(1):143-146.
41. Lave T., Dupin S., Schmitt C., et al. Integration of in vitro data into allometric scaling to predict hepatic metabolic clearance in man:application of 10 extensively metabolized drugs[J]. J Pharm Sci,1997,86(5):584-590.
42. Aranzazu-Partearroyo M., Ostolaza H., Goni F.M., et al. Surfactant-induced cell toxicity and cell lysis. A study using B16 melanoma cells[J]. Biochem Pharmacol,1990, 40(6):1323-1328.
43.任秀华,斯陆勤,曹磊等.单次不同剂量PEG 400对大鼠体内细胞色素P450 3A活 性的影响[J].中国药学杂志,2009,44(2)：345-348.
44.任秀华,斯陆勤,曹磊等.多次不同剂量PEG 400对大鼠体内细胞色素P450 3A活性的影响[J].中国医院药学杂志,2008,28(22)：1912-1916.
45. Cotreau-Bibbo M.M., Von-Moltke L.L., Greenblatt D.J., et al. Influence of polyethylene glycol and acetone on the in vitro biotransformation of tamoxifen and alprazolam by human liver microsomes[J]. J Pharm Sci,1996,85(11):1180-1185.
46. Iwase M., Kurate R., Ehana R., et al. Evaluation of the effects of hydrophilic organic solvents on CYP3A-mediated drug-drug interaction in vitro[J]. Hum Exp Toxicol,2006, 25(12):715-721.
47. Chauret N., Gauthier A., Nicoll-Griffith D.A., et al. Effect of common organic solvents on in vitro cytochrome P450-mediated metabolic activities in human liver microsomes[J]. Drug Metab Dispos,1998,26(1):1-4.
48. Hickman D., Wang J.P., Wang Y., et al. Evaluation of the selectivity of in vitro probes and suitability of organic solvents for the measurement of human cytochrome P450 monooxygenase activities[J]. Drug Metab Dispos,1998,26(3):207-215.
49. Huang J.G., Si L.Q., Jiang L.L., et al. Effect of pluronic F68 block copolymer on P-glycoprotein transport and CYP3A4 metabolism[J]. Int J Pharm,2008,356(1-2): 351-353.
50.赵冬梅,李燕.药物代谢研究在新药开发中的作用[J].药学学报,2000,35(2)：156-160.
51. Riordan S., Williams R. Bioartificial livers support:developments in hepatoeyte culture and bioreactor design[J]. Br Med Bull,1997,53(4):730-734.
52. Wrighton S.A., Ring B. J., VandenBranden M. The use of in vitro metabolism techniques in the planning and interpretation of drug safety studies[J]. Toxicol. Pathol.,1995,23(2): 199-208.
53. Wienkers L.C. Factors confounding the successful extrapolation of in vitro CYP3A inhibition information to the in vivo condition[J]. Eur J Pharm Sci,2002,15(3):239-242.
54. Backman J.T., Maenpaa J., Belle D.J., et al. Lack of correlation between in vitro and in vivo studies on the effects of tangeretin and tangerine juice on midazolam hydroxylation[J]. Clin Pharmacol Ther,2000,67(4):382-390.
55. Patki K.C., Von Moltke L.L., Greenblatt D.J. In vitro metabolism of midazolam, triazolam, Nifedipine, and testosterone by human liver microsomes and recombinant cyochromes P450:role of CYP3A4 and CYP3A5[J]. Drug Metab Dispos,2003,31(7): 938-945.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |