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首页> 外文期刊>The Journal of toxicological sciences >Simultaneous pharmacokinetics assessment of caffeine, warfarin, omeprazole, metoprolol, and midazolam intravenously or orally administered to Microminipigs
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Simultaneous pharmacokinetics assessment of caffeine, warfarin, omeprazole, metoprolol, and midazolam intravenously or orally administered to Microminipigs

机译：对Microminipigs静脉或口服咖啡因，华法林，奥美拉唑，美托洛尔和咪达唑仑的同时药代动力学评估

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Small minipigs (Microminipig, registered as a novel variety of pig in Japan) were developed for use in non-clinical pharmacological/toxicological studies for new drug development. To assess the pharmacokinetics of selective substrates of human cytochrome P450s in Microminipigs, caffeine (human P450 1A2), warfarin (P450 2C9), omeprazole (P450 2C19), metoprolol (P450 2D6), and midazolam (P450 3A) were administered in combination, intravenously (0.20 mg kg?1) or orally (1.0 mg kg?1). Plasma samples obtained, up to 24 hr after dosing, from four male and four female Microminipigs were analyzed by liquid chromatography tandem mass spectrometry to estimate typical pharmacokinetic parameters for each analyte. Bioavailabilities were approximately 80% for caffeine and warfarin, but less than 10% for omeprazole, metoprolol, and midazolam. No significant differences were noted, for the five probes, in area under the plasma concentration-time curve and peak plasma concentration values obtained from male and female Microminipigs. Clearance of caffeine, warfarin, omeprazole or midazolam in vivo , mediated mainly by cytochrome P450s 1A, 2C or 3A in Microminipigs, was similar to data reported for human. However, metoprolol metabolism, mediated by P450 2D enzymes in Microminipigs, was faster than reported for in vivo human kinetic parameters and in vitro in a human liver microsomal system. The results of this study suggest that the Microminipig is a suitable animal model for use in biological experiments for comparisons of pharmacokinetics of drugs in humans. The five-probes in combination used in this study demonstrate the disposition of typical P450 drugs in Microminipigs in vivo , with the aim of use in non-clinical pharmacological/toxicological studies.
机译：小型小型猪（Microminipig，在日本注册为新型猪）被开发用于新药开发的非临床药理/毒理学研究。为了评估Microminipigs中人类细胞色素P450选择性底物的药代动力学，将咖啡因（人类P450 1A2），华法林（P450 2C9），奥美拉唑（P450 2C19），美托洛尔（P450 2D6）和咪达唑仑（P450 3A）联合给药，静脉注射（0.20 mg kg ？1 ） 或口服（1.0 mg kg ？1 ）。在给药后直至24小时，通过液相色谱串联质谱法分析了来自四个雄性和四个雌性Microminipigs的血浆样品，以估计每种分析物的典型药代动力学参数。咖啡因和华法林的生物利用度约为80％，但奥美拉唑，美托洛尔和咪达唑仑的生物利用度不到10％。对于这五个探针，在血浆浓度-时间曲线下的面积和从男性和女性Microminipigs获得的峰值血浆浓度值下均未发现明显差异。主要由Microminipigs中的细胞色素P450 1A，2C或3A介导的体内咖啡因，华法林，奥美拉唑或咪达唑仑的清除与报道的人类数据相似。但是，由Microminipigs中的P450 2D酶介导的美托洛尔的代谢速度比体内人体动力学参数和人体肝脏微粒体系统体外报道的要快。这项研究的结果表明，Microminipig是一种适合用于生物学实验的动物模型，用于比较人类药物的药代动力学。本研究中使用的五种探针组合证明了典型的P450药物在体内的微量元素的分布，旨在用于非临床药理/毒理学研究。

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