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Human total clearance values and volumes of distribution of typical human cytochrome P450 2C9/19 substrates predicted by single-species allometric scaling using pharmacokinetic data sets from common marmosets genotyped for P450 2C19
Xenobiotica ( IF 1.8 ) Pub Date : 2021-01-17 , DOI: 10.1080/00498254.2020.1871113
Shogo Matsumoto 1 , Shotaro Uehara 2, 3 , Hidetaka Kamimura 2, 4 , Hiroshi Ikeda 5 , Satoshi Maeda 6 , Machiko Hattori 6 , Megumi Nishiwaki 7 , Kazuhiko Kato 1 , Hiroshi Yamazaki 3
Affiliation  

Abstract

  1. Common marmosets (Callithrix jacchus) are small non-human primates that genetically lack cytochrome P450 2C9 (CYP2C9). Polymorphic marmoset CYP2C19 compensates by mediating oxidations of typical human CYP2C9/19 substrates.

  2. Twenty-four probe substrates were intravenously administered in combinations to marmosets assigned to extensive or poor metaboliser (PM) groups by CYP2C19 genotyping. Eliminations from plasma of cilomilast, phenytoin, repaglinide, tolbutamide, and S-warfarin in the CYP2C19 PM group were significantly slow; these drugs are known substrates of human CYP2C8/9/19.

  3. Human total clearance values and volumes of distribution of the 24 test compounds were extrapolated using single-species allometric scaling with experimental data from marmosets and found to be mostly comparable with the reported values.

  4. Human total clearance values and volumes of distribution of 15 of the 24 test compounds similarly extrapolated using reported data sets from cynomolgus or rhesus monkeys were comparable to the present predicted results, especially to those based on data from PM marmosets.

  5. These results suggest that single-species allometric scaling using marmosets, being small, has advantages over multiple-species-based allometry and could be applicable for pharmacokinetic predictions at the discovery stage of drug development.



中文翻译:

人类总清除率值和典型人类细胞色素P450 2C9 / 19底物的分布量,是通过单物种异速生长规模使用基因型P450 2C19的普通mar猴的药代动力学数据集预测的

抽象的

  1. 普通mar猴(Callithrix jacchus)是非人类的小型灵长类动物,在遗传上缺乏细胞色素P450 2C9CYP2C9)。多态mar猴CYP2C19通过介导典型的人CYP2C9 / 19底物的氧化来补偿。

  2. 通过CYP2C19基因分型,将二十四种探针底物组合静脉内施用给分配给广泛或不良代谢者(PM)组的mar猴。CYP2C19 PM组血浆中cilomilast,苯妥英钠,瑞格列奈,tolbutamide和S- warfarin的清除作用明显减慢。这些药物是人类CYP2C8 / 9/19的已知底物。

  3. 使用来自mar猴的实验数据,使用单物种异构缩放法推断了人类总清除率值和24种测试化合物的分布体积,发现它们与报告值基本相当。

  4. 使用食蟹猴或恒河猴的报告数据集类似推算出的24种测试化合物中的15种的人类总清除率值和分布体积与当前预测结果相当,特别是与基于PM mos猴的数据得出的结果相当。

  5. 这些结果表明,使用mar猴的单物种异体缩放比例较小,比基于多物种的异体缩放具有优势,并且可以在药物开发的发现阶段用于药代动力学预测。

更新日期:2021-03-12
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