Species Differences in Carboxylesterases Among Humans, Cynomolgus Monkeys, and Mice in the Hydrolysis of Atorvastatin Derivatives

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Masato Takahashi, Sachiko Sakai, Kohei Takahashi, Masakiyo Hosokawa
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引用次数: 0

Abstract

Nonclinical trials are crucial for assessing pharmaceutical efficacy and safety prior to clinical trials. However, disparities in drug metabolism between humans and animals complicate extrapolating animal data to humans. Variability in drug-metabolizing enzymes, such as carboxylesterases (CESs), contributes to differences in drug kinetics. This study aimed to explore species disparities in CES substrate specificity among humans (hCES1), mice (mCES1), and cynomolgus monkeys (mfCES1) using diverse atorvastatin ester derivatives. This study measured hydrolysis rates of 30 atorvastatin derivatives. Metabolites were identified via HPLC with an internal standard, measuring rates per unit time and enzyme amount. Enzyme metabolic activity was compared using hydrolysis rates. The structure of the alkoxy group resulted in differences ranging from approximately half to 8.97-fold between hCES1 and mCES1 and differences ranging from similar to 15.82-fold between hCES1 and mfCES1. Caution is warranted when extrapolating animal data to humans, especially for esters with diverse structures. Our focus on the alkoxy group structure highlights its impact on hydrolysis rates. Further investigation into species differences among CES enzymes is essential for accurate translational research.

人类、食蟹猴和小鼠中羧酸酯酶水解阿托伐他汀衍生物的物种差异。
在临床试验之前,非临床试验对于评估药物的有效性和安全性至关重要。然而,人类和动物之间药物代谢的差异使得将动物数据外推到人类身上变得复杂。药物代谢酶的可变性,如羧酸酯酶(CESs),有助于药物动力学的差异。本研究旨在利用不同的阿托伐他汀酯衍生物,探讨人类(hCES1)、小鼠(mCES1)和食蟹猴(mfCES1)之间CES底物特异性的物种差异。本研究测量了30种阿托伐他汀衍生物的水解率。用高效液相色谱法鉴定代谢产物,内标,测定单位时间速率和酶量。用水解速率比较酶代谢活性。烷氧基基团的结构导致hCES1和mCES1之间的差异约为一半至8.97倍,hCES1和mfCES1之间的差异约为15.82倍。当将动物数据外推到人类身上时,需要谨慎,特别是对于具有不同结构的酯类。我们对烷氧基结构的关注突出了它对水解速率的影响。进一步研究CES酶的物种差异对准确的转化研究至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.60
自引率
0.00%
发文量
35
审稿时长
6-12 weeks
期刊介绍: Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes: - animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites, - in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man - studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition, - simulation and modeling in drug discovery and development - theoretical treatises - includes themed issues and reviews and exclude manuscripts on - bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation - analytical methods
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