以洛伐他汀为典型药物研究巴马香猪和人代谢的异同
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摘要
小型猪的心脏与循环系统与人类相似,易患心血管疾病,因此在作为人类心血管系统动物模型方面独具优势。应用小型猪复制的人类心血管系统疾病动物模型与人类疾病高度相似,利用其研究心血管药物的药动学参数,可以很好指导药物的临床应用。此外,小型猪是CYP 3A4代谢药物无需诱导的良好动物模型。研究发现小型猪肝微粒体中存在与人CYP 3A家族相似的酶,序列分析显示小型猪CYP 3A与人的CYP 3A4有60%的序列同源性,说明小型猪作为药物研究,尤其是人CYP 3A4代谢的心血管药物安全性评价实验动物具有良好前景。但迄今为止,还没有比较系统的研究资料。
我国具有丰富的小型猪资源,其中巴马香猪近交程度高、被毛呈白色、耐近交、遗传稳定、个体表型一致,并积累了丰富的解剖、生理生化及基础生物学特性背景资料。但国内小型猪很少应用于药物评价研究,其原因在于我国的基础研究薄弱,进行药物安全性评价方面的应用基础研究缺乏,尤其受到药物代谢研究资料不足的限制,使我国丰富的小型猪资源优势得不到充分发挥。
因此,我们选用一种临床上用于治疗动脉粥样硬化并可被细胞色素P450 3A4代谢的药物——洛伐他汀作为典型药物,以我国独特的小型猪资源——巴马香猪作为实验动物,从常规的药物体内过程(分布和排泄)及长期毒性,微粒体亚细胞水平(代谢活性的比较和代谢产物的分析)到单一代谢酶(细胞色素P450 3A)逐层深入研究,希望形成一套完整的CYP 3A4代谢的心血管药物的资料,填补国内小型猪药物代谢研究不足的空白,积累小型猪作为人CYP 3A4代谢的心血管药物安全性评价实验动物的基础研究数据和实验依据;并与人和其他实验动物进行比较研究,突出小型猪在人CYP 3A4代谢的心血管药物中的优势,为巴马香猪在药物安全性评价中的应用提供理论支持,以此推进小型猪在新药安全评价中的应用。
研究内容和结果:
逐层对洛伐他汀在巴马香猪体内的代谢进行研究,并与人和其他实验动物各方面的实验数据和文献报道资料进行比较,获得比较全面的巴马香猪在人CYP 3A4代谢的心血管药物中研究的实验数据。
(1)洛伐他汀在巴马香猪体内的分布排泄研究
以抗动脉粥样硬化药物洛伐他汀为模型药,选择健康6月龄雄性巴马香猪为实验对象,经灌胃途径给药(45 mg/kg或2.4 mg/kg),采用RP-HPLC方法测定各组织及体液中的药物浓度,并对其组织分布和排泄过程进行研究;通过透析法测定血浆蛋白结合率;对LV和HA在血浆中转化率进行测定;所有结果与不同种属实验动物进行比较分析。给药后,洛伐他汀快速分布到贲门、胃、小肠、肝、大肠、胰、前列腺、肺、肾、心、肌肉、睾丸、肾上腺、膀胱、脑和脾。以胃、肠、肝组织中药物浓度较高,说明药物在小型猪体内具有明显的胃吸收和肝脏大量摄取的过程;药物在小型猪体内能通过大脑屏障;低剂量下的重复给药没有在小型猪体内形成蓄积;96 h尿中累积排泄量为给药量的7.4%,原形药经胆汁及粪排泄量达到80%以上;小型猪和人血浆的LV与HA转化极其相似,血浆蛋白结合率为95%以上。
(2)洛伐他汀在巴马香猪体内的长期毒性研究
以抗动脉粥样硬化药物洛伐他汀为模型药,选择健康6月龄雄性巴马香猪为实验对象,经灌胃途径给药(12 mg·kg-1和135 mg·kg-1),对巴马香猪进行为期6周的长期毒性实验,观察给药后的临床表现、血液学、血生化、脏器系数和组织病理学等指标进行药效和毒性的评价。
主要毒性反应在135 mg·kg-1组,给药后巴马香猪出现了竖毛、腹泻等症状,总采食量下降,体重减轻;血液血检查显示白细胞总数有所增加,红细胞总数、血红蛋白含量和血小板计数明显下降;血液生化检查显示ALT、AST、ALP和CK升高2-10倍,肌酐和尿素有所升高;总胆固醇、低密度脂蛋白、总胆固醇/高密度脂蛋白和低密度脂蛋白/高密度脂蛋白的比率明显降低,血浆甘油三脂适度降低;组织病理学切片显示巴马香猪出现了与人相似的肝肾病理改变。
(3)洛伐他汀在巴马香猪中的体外代谢和主要代谢产物研究
选择人体CYP 3A4代谢的典型底物硝苯地平为阳性对照,制备巴马香猪、人和大鼠的肝微粒体,进行洛伐他汀在巴马香猪肝微粒体中的酶动力学研究,并与人体和大鼠肝微粒体比较;配合体内外代谢产物研究,以人肝微粒体P450酶3A亚型的选择性抑制剂酮康唑(KCZ)和三乙酰竹桃霉素(TAO)和诱导剂利福平,对小型猪CYP 3A亚型的探针反应的抑制和诱导效果进行了评价;利用UV、HPLC和MS的检测手段对洛伐他汀在巴马香猪体内外的代谢产物进行了分析检测;并与人和常用实验动物大鼠相应结果进行了比较,从巴马香猪体内外代谢水平进行综合评估。巴马香猪肝微粒体代谢洛伐他汀的酶动力学变化与人体更相似;人体CYP 3A特异性抑制剂均可以显著抑制三者的代谢,但是巴马香猪代谢速率下降程度与人体接近;利福平可以诱导巴马香猪中类似人体CYP 3A4酶的产生,使猪体内CYP 3A4底物的代谢活性得到增加;巴马香猪在洛伐他汀体内外的代谢产物与人相当接近,在体外微粒体中分别生成主要代谢产物6′-β-羟基-LV(遇酸变构为3′-羟基-异-Δ4′,5′-LV)和6′-挂亚甲基LV,在体内胆汁中,pH5.0温和水解下生成其羟酸形式;在巴马香猪CYP 3A底物代谢反应活性测定、选择性抑制剂和诱导剂抑制诱导反应效果、代谢产物的确定三个层面,与人和其他实验动物进行比较,综合评定使研究结果得到多重验证。
(4)巴马香猪中CYP 3A29代谢酶的异源表达和活性鉴定
选择巴马香猪体内与人体CYP 3A4可能具有相同代谢特征的细胞色素P450 3A29,进行大肠杆菌的异源表达,通过电泳、免疫印记及相关的活性测定,进一步提供巴马香猪类似代谢酶的代谢特点和与人CYP 3A4相似的理论资料,比较人体CYP 3A4和巴马香猪细胞色素P450 3A29的活性和相关代谢反应。
通过去除N端疏水膜定位信号序列设计引物,分别利用pGEM-T载体、pET28b表达载体和DH5α、DE3菌株对CYP 3A29基因进行扩增、克隆及表达,通过SDS-PAGE和Western blot验证,获得CYP 3A29的大肠杆菌重组子;优化了蛋白表达条件,在除N端疏水序列/TB/10μM IPTG/25℃的条件下,获得的可溶性蛋白最多,活性最高;重组子具有人CYP 3A4硝苯地平活性,与亚细胞微粒体水平的体外代谢模型结果相互验证。
结论:
1.巴马香猪是较理想的用于洛伐他汀类心血管药物药代动力学研究的实验动物。洛伐他汀在巴马香猪体内的过程与人类似。
2.巴马香猪可以用作洛伐他汀类心血管药物毒性研究的实验动物。洛伐他汀给药后,巴马香猪能敏感的反映洛伐他汀的大部分潜在毒性。
3.巴马香猪肝微粒体适用于作为研究人CYP 3A4药物代谢途径和特征的体外实验动物模型。在巴马香猪CYP 3A底物代谢反应活性测定、选择性抑制剂和诱导剂的作用效果、代谢产物的确定三个层面,与人基本一致。
4.巴马香猪适用于作为人CYP 3A酶代谢的相关药物研究的良好动物模型:通过大肠杆菌异源表达出巴马香猪CYP 3A29蛋白,并具有人CYP 3A4硝苯地平活性。
本论文的完成将形成了以洛伐他汀作为典型药物,以巴马香猪作为实验动物的一套完整药物代谢数据;形成巴马香猪与人及其他实验动物比较的研究资料;从代谢和毒性方面说明小型猪是人CYP 3A4代谢的心血管药物安全性评价的较好模型动物。
Research objective and background:
Minipig was a good animal model for research on the cardiovascular deseases of human, because its heart and cardiovascular system were very similar to human. Minipig models of cardiovascular system diseases are closely resemble those of human. Thus, clinical application of cardiovascular drugs could be well guided using minipigs model to study pharmacokenetic. Additionally, minipig was also considered as a good model of human CYP 3A4 without induction. It has been reported there were similar enzymes as human CYP 3A4/5 in liver microsomes of minipigs. Sequences analysis indicated the CYP 3A of minipig had 60% homologous with human CYP 3A4. These studies suggested minipigs have a predicted prospect as experimental animals for evaluting drugs which were metabolized by human CYP 3A4. However, no systematic research was carried out.
China has copious resource of minpigs. Bama miniature pigs were found in China with many advantages, such as high extent of inbreeding, white hair, bearing inbreeding, stable heredity and a consistent phenotype, and were proved to be a superior animal models. Additionally, there are much background information about anatomy, physiology, biochemistry and basic biological characteristics. In China, however, they have never been used in drug safety evaluation due to the scanty application research background on pharmacology and toxicology evaluation.
In our previous study, lovastatin, a basic drug widely used in curing AS, was chosed as model drug to investigate its metabolism in Bama miniature pigs completely. In this study, we further used this drug to investigate the disposition (distribution and excretion) and long-term toxicity in vivo, metabolism of microsome (comparing activity and analysising metabolites) and main metabolic enzyme (cytochrome P450 3A) in miniature pigs. All data were compared with human and other animals.
Contents and results of the research:
(1) Distribution and excretion of lovastatin in Bama miniature pigs.
6-month male Bama minipigs were intragastric administrated (45 mg/kg or 2.4 mg/kg). The concentration of lovastatin in tissues and body-fluid in 6-month old male Bama minipigs after oral administration were detected by RP-HPLC. The distribution-excretion process and transformation efficiency of LV-HA were investigated. Protein binding was determined by dialysis method. All results were compared with different experimental animals.
Lovastatin was showed to be widely distributed in many tissues after i.g. dose of 45 mg/kg. The higher level of lovastatin was found in the stomach, intestine and liver. The concentrations in stomach, small intestine, liver, heart, adrenal and bladder at 1 h were higher than those of 4 h. The drug was found in blood-brain barrier of Bama miniature pig. 7.4% of the given dose was excreted in unchanged form in urine within 96 h. More than 80% was excreted in bile and feces within 96 h. The plasma protein binding ratio was higher than 95% and transformation efficiency of LV-HA was very similar between human and pig plasma.
(2) Long-term toxicity test of lovastatin in Bama miniature pigs.
6-month male Bama minipigs were randomly divided into two dose groups(12 mg·kg-1 and 135 mg·kg-1)and a blank group. The drug was given once a day for 42 successive days. Manifestation and behaviors, hematology, blood chemistry and histopathology were detected.
The results revealed that 135 mg·kg-1 dose caused serious toxicity. The main toxic manifestations were piloerection and diarrhea, body weight loss and declined foraging quantity. Compared to control, total white cell count increased, however red blood count and hemoglobin and blood platelets count declined. ALT、AST、ALP and CK were increased 2-10 fold. Lovastatin has been shown to be highly effective in reducing plasma total-C, LDL, total-C/HDL ratio and LDL/HDL ratio. In addition, lovastatin modestly decreased plasma TG.
The pathological histology analysis result showed that there were some morphological abnormalities and characteristic pathological change in the major target organ, liver and kidney.
(3) Lovastatin metabolism of liver microsomes and essential metabolites in Bama miniature pigs
To evaluate the feasibility of Bama miniature pigs to be used as a model on pharmacokenetic properties of CYP 3A4, we compared the enzymatic kinetics of lovastatin and nifedipine in liver microsomes of Bama miniature pigs with that of human and rats. We evaluated the biotransformation activity in the minipig liver microsomes and compare with those of human and rat. The inhibitory and induction effects were determined by using chemical inhibitor and inductor specific to the CYP 3A in human. Metabolites of lovastatin were detected by UV, HPLC and MS.
The enzymatic kinetics of minipig liver microsomes was more close to human than rats. The metabolism of lovastatin in three various genera was significantly inhibited by ketoconazole but the descendent rate of metabolism in pigs was similar to human. The average activity levels of nifedipine of Bama miniature pigs increased remarkablely when treated with rifampicin. Otherwise, the metabolites of lovastatin in vitro and in vivo of pigs were also close to that of human.
(4) Expression of CYP 3A29 in Escherichia coli
A P450 gene (3A29) from Bama miniature pigs, which was homologous to human CYP 3A4 gene, was successfully expressed in Escherichia coli. The expressed CYP 3A29 was confirmed by SDS-PAGE and western blot analysis. We investigated the effects of culture broth, temperature, IPTG concentration and additives on the expression level of CYP 3A29. The metabolism characteristics of CYP 3A29 expressed in E. coli were compared with those from human.
Through constructed the truncated CYP 3A29 gene without 28 N-terminal amino acids (membrane-anchor signal peptide), we obtained active CYP 3A29 protein in cytoplasmic fraction of E. coli cells. We found the optimal conditions to produce active CYP 3A29 were to induce E. coli cells contained pET28b-3A29 with 10mM IPTG in TB broth for 10h at 25℃. 3A29 produced in E. coli has the oxidation activity of Nifedipine (NOD), which was the same as that in liver microsomes of pigs.
Conclusions:
(1) Our results showed the distribution-excretion, plasma protein binding ratio and transformation efficiency of LV-HA of lovastatin in the Bama minipigs were similar to those in humans. Thus, it could be concluded that Bama miniature pigs should be an ideal experimental animal of pharmacokinetics for cardiovascular drugs similar to lovastatin.
(2) Bama miniature pigs could sensitively show toxic reactions which were observed in clinical therapy of lovastatin.
(3) Compared with rats, Bama miniature pigs were more close to humans in the biotransformation activity of CYP 3A and the inhibitory and induction effects by chemical inhibitor and inductor specific to the CYP 3A. Therefore, Bama miniature pigs are suitable for the pharmacological studies relating to human CYP 3A.
(4) The CYP 3A29 enzyme of Bama miniature pigs expressed in E. coli showed the oxidation activity of Nifedipine as human CYP 3A4. This indicated Bama minipig was a suitable animal model for human drugs which was metabolized by CYP 3A.
Combined these results, we can collecte a complete data about metabolism of lovastatin in Bama miniature pigs. We evaluate the feasibility of Bama miniature pig to be used as a good model on safety evaluation of cardiovascular drugs which was metabolismed by human CYP 3A4.
我国具有丰富的小型猪资源,其中巴马香猪近交程度高、被毛呈白色、耐近交、遗传稳定、个体表型一致,并积累了丰富的解剖、生理生化及基础生物学特性背景资料。但国内小型猪很少应用于药物评价研究,其原因在于我国的基础研究薄弱,进行药物安全性评价方面的应用基础研究缺乏,尤其受到药物代谢研究资料不足的限制,使我国丰富的小型猪资源优势得不到充分发挥。
因此,我们选用一种临床上用于治疗动脉粥样硬化并可被细胞色素P450 3A4代谢的药物——洛伐他汀作为典型药物,以我国独特的小型猪资源——巴马香猪作为实验动物,从常规的药物体内过程(分布和排泄)及长期毒性,微粒体亚细胞水平(代谢活性的比较和代谢产物的分析)到单一代谢酶(细胞色素P450 3A)逐层深入研究,希望形成一套完整的CYP 3A4代谢的心血管药物的资料,填补国内小型猪药物代谢研究不足的空白,积累小型猪作为人CYP 3A4代谢的心血管药物安全性评价实验动物的基础研究数据和实验依据;并与人和其他实验动物进行比较研究,突出小型猪在人CYP 3A4代谢的心血管药物中的优势,为巴马香猪在药物安全性评价中的应用提供理论支持,以此推进小型猪在新药安全评价中的应用。
研究内容和结果:
逐层对洛伐他汀在巴马香猪体内的代谢进行研究,并与人和其他实验动物各方面的实验数据和文献报道资料进行比较,获得比较全面的巴马香猪在人CYP 3A4代谢的心血管药物中研究的实验数据。
(1)洛伐他汀在巴马香猪体内的分布排泄研究
以抗动脉粥样硬化药物洛伐他汀为模型药,选择健康6月龄雄性巴马香猪为实验对象,经灌胃途径给药(45 mg/kg或2.4 mg/kg),采用RP-HPLC方法测定各组织及体液中的药物浓度,并对其组织分布和排泄过程进行研究;通过透析法测定血浆蛋白结合率;对LV和HA在血浆中转化率进行测定;所有结果与不同种属实验动物进行比较分析。给药后,洛伐他汀快速分布到贲门、胃、小肠、肝、大肠、胰、前列腺、肺、肾、心、肌肉、睾丸、肾上腺、膀胱、脑和脾。以胃、肠、肝组织中药物浓度较高,说明药物在小型猪体内具有明显的胃吸收和肝脏大量摄取的过程;药物在小型猪体内能通过大脑屏障;低剂量下的重复给药没有在小型猪体内形成蓄积;96 h尿中累积排泄量为给药量的7.4%,原形药经胆汁及粪排泄量达到80%以上;小型猪和人血浆的LV与HA转化极其相似,血浆蛋白结合率为95%以上。
(2)洛伐他汀在巴马香猪体内的长期毒性研究
以抗动脉粥样硬化药物洛伐他汀为模型药,选择健康6月龄雄性巴马香猪为实验对象,经灌胃途径给药(12 mg·kg-1和135 mg·kg-1),对巴马香猪进行为期6周的长期毒性实验,观察给药后的临床表现、血液学、血生化、脏器系数和组织病理学等指标进行药效和毒性的评价。
主要毒性反应在135 mg·kg-1组,给药后巴马香猪出现了竖毛、腹泻等症状,总采食量下降,体重减轻;血液血检查显示白细胞总数有所增加,红细胞总数、血红蛋白含量和血小板计数明显下降;血液生化检查显示ALT、AST、ALP和CK升高2-10倍,肌酐和尿素有所升高;总胆固醇、低密度脂蛋白、总胆固醇/高密度脂蛋白和低密度脂蛋白/高密度脂蛋白的比率明显降低,血浆甘油三脂适度降低;组织病理学切片显示巴马香猪出现了与人相似的肝肾病理改变。
(3)洛伐他汀在巴马香猪中的体外代谢和主要代谢产物研究
选择人体CYP 3A4代谢的典型底物硝苯地平为阳性对照,制备巴马香猪、人和大鼠的肝微粒体,进行洛伐他汀在巴马香猪肝微粒体中的酶动力学研究,并与人体和大鼠肝微粒体比较;配合体内外代谢产物研究,以人肝微粒体P450酶3A亚型的选择性抑制剂酮康唑(KCZ)和三乙酰竹桃霉素(TAO)和诱导剂利福平,对小型猪CYP 3A亚型的探针反应的抑制和诱导效果进行了评价;利用UV、HPLC和MS的检测手段对洛伐他汀在巴马香猪体内外的代谢产物进行了分析检测;并与人和常用实验动物大鼠相应结果进行了比较,从巴马香猪体内外代谢水平进行综合评估。巴马香猪肝微粒体代谢洛伐他汀的酶动力学变化与人体更相似;人体CYP 3A特异性抑制剂均可以显著抑制三者的代谢,但是巴马香猪代谢速率下降程度与人体接近;利福平可以诱导巴马香猪中类似人体CYP 3A4酶的产生,使猪体内CYP 3A4底物的代谢活性得到增加;巴马香猪在洛伐他汀体内外的代谢产物与人相当接近,在体外微粒体中分别生成主要代谢产物6′-β-羟基-LV(遇酸变构为3′-羟基-异-Δ4′,5′-LV)和6′-挂亚甲基LV,在体内胆汁中,pH5.0温和水解下生成其羟酸形式;在巴马香猪CYP 3A底物代谢反应活性测定、选择性抑制剂和诱导剂抑制诱导反应效果、代谢产物的确定三个层面,与人和其他实验动物进行比较,综合评定使研究结果得到多重验证。
(4)巴马香猪中CYP 3A29代谢酶的异源表达和活性鉴定
选择巴马香猪体内与人体CYP 3A4可能具有相同代谢特征的细胞色素P450 3A29,进行大肠杆菌的异源表达,通过电泳、免疫印记及相关的活性测定,进一步提供巴马香猪类似代谢酶的代谢特点和与人CYP 3A4相似的理论资料,比较人体CYP 3A4和巴马香猪细胞色素P450 3A29的活性和相关代谢反应。
通过去除N端疏水膜定位信号序列设计引物,分别利用pGEM-T载体、pET28b表达载体和DH5α、DE3菌株对CYP 3A29基因进行扩增、克隆及表达,通过SDS-PAGE和Western blot验证,获得CYP 3A29的大肠杆菌重组子;优化了蛋白表达条件,在除N端疏水序列/TB/10μM IPTG/25℃的条件下,获得的可溶性蛋白最多,活性最高;重组子具有人CYP 3A4硝苯地平活性,与亚细胞微粒体水平的体外代谢模型结果相互验证。
结论:
1.巴马香猪是较理想的用于洛伐他汀类心血管药物药代动力学研究的实验动物。洛伐他汀在巴马香猪体内的过程与人类似。
2.巴马香猪可以用作洛伐他汀类心血管药物毒性研究的实验动物。洛伐他汀给药后,巴马香猪能敏感的反映洛伐他汀的大部分潜在毒性。
3.巴马香猪肝微粒体适用于作为研究人CYP 3A4药物代谢途径和特征的体外实验动物模型。在巴马香猪CYP 3A底物代谢反应活性测定、选择性抑制剂和诱导剂的作用效果、代谢产物的确定三个层面,与人基本一致。
4.巴马香猪适用于作为人CYP 3A酶代谢的相关药物研究的良好动物模型:通过大肠杆菌异源表达出巴马香猪CYP 3A29蛋白,并具有人CYP 3A4硝苯地平活性。
本论文的完成将形成了以洛伐他汀作为典型药物,以巴马香猪作为实验动物的一套完整药物代谢数据;形成巴马香猪与人及其他实验动物比较的研究资料;从代谢和毒性方面说明小型猪是人CYP 3A4代谢的心血管药物安全性评价的较好模型动物。
Research objective and background:
Minipig was a good animal model for research on the cardiovascular deseases of human, because its heart and cardiovascular system were very similar to human. Minipig models of cardiovascular system diseases are closely resemble those of human. Thus, clinical application of cardiovascular drugs could be well guided using minipigs model to study pharmacokenetic. Additionally, minipig was also considered as a good model of human CYP 3A4 without induction. It has been reported there were similar enzymes as human CYP 3A4/5 in liver microsomes of minipigs. Sequences analysis indicated the CYP 3A of minipig had 60% homologous with human CYP 3A4. These studies suggested minipigs have a predicted prospect as experimental animals for evaluting drugs which were metabolized by human CYP 3A4. However, no systematic research was carried out.
China has copious resource of minpigs. Bama miniature pigs were found in China with many advantages, such as high extent of inbreeding, white hair, bearing inbreeding, stable heredity and a consistent phenotype, and were proved to be a superior animal models. Additionally, there are much background information about anatomy, physiology, biochemistry and basic biological characteristics. In China, however, they have never been used in drug safety evaluation due to the scanty application research background on pharmacology and toxicology evaluation.
In our previous study, lovastatin, a basic drug widely used in curing AS, was chosed as model drug to investigate its metabolism in Bama miniature pigs completely. In this study, we further used this drug to investigate the disposition (distribution and excretion) and long-term toxicity in vivo, metabolism of microsome (comparing activity and analysising metabolites) and main metabolic enzyme (cytochrome P450 3A) in miniature pigs. All data were compared with human and other animals.
Contents and results of the research:
(1) Distribution and excretion of lovastatin in Bama miniature pigs.
6-month male Bama minipigs were intragastric administrated (45 mg/kg or 2.4 mg/kg). The concentration of lovastatin in tissues and body-fluid in 6-month old male Bama minipigs after oral administration were detected by RP-HPLC. The distribution-excretion process and transformation efficiency of LV-HA were investigated. Protein binding was determined by dialysis method. All results were compared with different experimental animals.
Lovastatin was showed to be widely distributed in many tissues after i.g. dose of 45 mg/kg. The higher level of lovastatin was found in the stomach, intestine and liver. The concentrations in stomach, small intestine, liver, heart, adrenal and bladder at 1 h were higher than those of 4 h. The drug was found in blood-brain barrier of Bama miniature pig. 7.4% of the given dose was excreted in unchanged form in urine within 96 h. More than 80% was excreted in bile and feces within 96 h. The plasma protein binding ratio was higher than 95% and transformation efficiency of LV-HA was very similar between human and pig plasma.
(2) Long-term toxicity test of lovastatin in Bama miniature pigs.
6-month male Bama minipigs were randomly divided into two dose groups(12 mg·kg-1 and 135 mg·kg-1)and a blank group. The drug was given once a day for 42 successive days. Manifestation and behaviors, hematology, blood chemistry and histopathology were detected.
The results revealed that 135 mg·kg-1 dose caused serious toxicity. The main toxic manifestations were piloerection and diarrhea, body weight loss and declined foraging quantity. Compared to control, total white cell count increased, however red blood count and hemoglobin and blood platelets count declined. ALT、AST、ALP and CK were increased 2-10 fold. Lovastatin has been shown to be highly effective in reducing plasma total-C, LDL, total-C/HDL ratio and LDL/HDL ratio. In addition, lovastatin modestly decreased plasma TG.
The pathological histology analysis result showed that there were some morphological abnormalities and characteristic pathological change in the major target organ, liver and kidney.
(3) Lovastatin metabolism of liver microsomes and essential metabolites in Bama miniature pigs
To evaluate the feasibility of Bama miniature pigs to be used as a model on pharmacokenetic properties of CYP 3A4, we compared the enzymatic kinetics of lovastatin and nifedipine in liver microsomes of Bama miniature pigs with that of human and rats. We evaluated the biotransformation activity in the minipig liver microsomes and compare with those of human and rat. The inhibitory and induction effects were determined by using chemical inhibitor and inductor specific to the CYP 3A in human. Metabolites of lovastatin were detected by UV, HPLC and MS.
The enzymatic kinetics of minipig liver microsomes was more close to human than rats. The metabolism of lovastatin in three various genera was significantly inhibited by ketoconazole but the descendent rate of metabolism in pigs was similar to human. The average activity levels of nifedipine of Bama miniature pigs increased remarkablely when treated with rifampicin. Otherwise, the metabolites of lovastatin in vitro and in vivo of pigs were also close to that of human.
(4) Expression of CYP 3A29 in Escherichia coli
A P450 gene (3A29) from Bama miniature pigs, which was homologous to human CYP 3A4 gene, was successfully expressed in Escherichia coli. The expressed CYP 3A29 was confirmed by SDS-PAGE and western blot analysis. We investigated the effects of culture broth, temperature, IPTG concentration and additives on the expression level of CYP 3A29. The metabolism characteristics of CYP 3A29 expressed in E. coli were compared with those from human.
Through constructed the truncated CYP 3A29 gene without 28 N-terminal amino acids (membrane-anchor signal peptide), we obtained active CYP 3A29 protein in cytoplasmic fraction of E. coli cells. We found the optimal conditions to produce active CYP 3A29 were to induce E. coli cells contained pET28b-3A29 with 10mM IPTG in TB broth for 10h at 25℃. 3A29 produced in E. coli has the oxidation activity of Nifedipine (NOD), which was the same as that in liver microsomes of pigs.
Conclusions:
(1) Our results showed the distribution-excretion, plasma protein binding ratio and transformation efficiency of LV-HA of lovastatin in the Bama minipigs were similar to those in humans. Thus, it could be concluded that Bama miniature pigs should be an ideal experimental animal of pharmacokinetics for cardiovascular drugs similar to lovastatin.
(2) Bama miniature pigs could sensitively show toxic reactions which were observed in clinical therapy of lovastatin.
(3) Compared with rats, Bama miniature pigs were more close to humans in the biotransformation activity of CYP 3A and the inhibitory and induction effects by chemical inhibitor and inductor specific to the CYP 3A. Therefore, Bama miniature pigs are suitable for the pharmacological studies relating to human CYP 3A.
(4) The CYP 3A29 enzyme of Bama miniature pigs expressed in E. coli showed the oxidation activity of Nifedipine as human CYP 3A4. This indicated Bama minipig was a suitable animal model for human drugs which was metabolized by CYP 3A.
Combined these results, we can collecte a complete data about metabolism of lovastatin in Bama miniature pigs. We evaluate the feasibility of Bama miniature pig to be used as a good model on safety evaluation of cardiovascular drugs which was metabolismed by human CYP 3A4.
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