Enhanced Platelet Response to Clopidogrel in Zucker Diabetic Fatty Rats due to Impaired Clopidogrel Inactivation by Carboxylesterase 1 and Increased Exposure to Active Metabolite

• Published in: Drug metabolism and disposition Vol. 47; no. 8; pp. 794 - 801
• Main Authors: Yao, Hongwei, Bai, Ruifeng, Ren, Tianming, Wang, Yani, Gu, Jingkai, Guo, Yingjie
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics, Inc 01.08.2019
• Subjects: Acids; Administration, Oral; Animal models; Animals; Blood Platelets - drug effects; Carboxylesterase; Carboxylesterase - metabolism; Clopidogrel; Clopidogrel - administration & dosage; Clopidogrel - pharmacokinetics; Cytochrome; Cytochrome P-450 Enzyme System - metabolism; Cytochromes; Deactivation; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - metabolism; Disease Models, Animal; Effectiveness; Enzymatic activity; Esterase; Fluorides; Humans; Inactivation; Liver; Male; Metabolism; Microsomes; mRNA; Pharmacokinetics; Platelet aggregation; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - pharmacokinetics; Proteins; Rats; Rats, Zucker; Rodents
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.118.085126

Clopidogrel (Clop), a thienopyridine antiplatelet prodrug, is metabolized by cytochrome P450s (CYPs) to an active metabolite, Clop-AM, and hydrolyzed by carboxylesterase (CES)1 to the inactive Clop-acid. Patients with type 2 diabetes (T2DM) tend to have a poor response to Clop due to reduced generation of Clop-AM. Whether a similar response occurs in the Zucker diabetic fatty (ZDF) rat, a commonly used animal model of T2DM, has not been explored. In this work, we compared ZDF and control rats for hepatic CES1- and CYP-mediated Clop metabolism; pharmacokinetics of Clop, Clop-AM, and Clop-acid; and the antiplatelet efficacy of Clop. In contrast to clinical findings, Clop-treated ZDF rats displayed significantly less (50%) maximum platelet aggregation at 4 hours than control rats; the enhanced efficacy was accompanied by higher formation of Clop-AM and lower formation of Clop-acid. In vitro studies showed that hepatic levels of CES1 protein and activity and Ces1e mRNA were significantly lower in ZDF than in control rats, as were the mRNA levels of CYP2B1/2, CYP2C11, and CYP3A2, and levels of CYP2B6-, CYP2C19-, and CYP3A4-related proteins and enzymatic activities in liver microsomes of ZDF rats. Interestingly, liver microsomes of ZDF rats produced higher levels of Clop-AM than that of control rats despite their lower CYP levels, although the addition of fluoride ion, an esterase inhibitor, enhanced Clop-AM formation in control rats more than in ZDF rats. These results suggest that the reduction in CES1-based Clop inactivation indirectly enhances Clop efficacy in ZDF rats by making more Clop available for CYP-mediated Clop-AM formation.