{"title":"Species Differences in Carboxylesterases Among Humans, Cynomolgus Monkeys, and Mice in the Hydrolysis of Atorvastatin Derivatives.","authors":"Masato Takahashi, Sachiko Sakai, Kohei Takahashi, Masakiyo Hosokawa","doi":"10.1002/bdd.70003","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":" ","pages":""},"PeriodicalIF":1.7000,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biopharmaceutics & Drug Disposition","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/bdd.70003","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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.
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