Antiplatelet agents aspirin and clopidogrel are hydrolyzed by distinct carboxylesterases, and clopidogrel is transesterificated in the presence of ethyl alcohol

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 319; no. 3; p. 1467
• Main Authors: Tang, Man, Mukundan, Madhu, Yang, Jian, Charpentier, Nathan, LeCluyse, Edward L, Black, Chris, Yang, Dongfang, Shi, Deshi, Yan, Bingfang
• Format: Journal Article
• Language: English
• Published: United States 01-12-2006
• Subjects: Animals; Aspirin - metabolism; Carboxylic Ester Hydrolases - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Central Nervous System Depressants - pharmacology; Chromatography, High Pressure Liquid; Esters - metabolism; Ethanol - pharmacology; Humans; Hydrolysis; In Vitro Techniques; Intestines - metabolism; Microsomes - metabolism; Microsomes, Liver - metabolism; Mutagenesis, Site-Directed; Platelet Aggregation Inhibitors - metabolism; Rats; Ticlopidine - analogs & derivatives; Ticlopidine - metabolism; Transfection
• ISSN: 0022-3565
• DOI: 10.1124/jpet.106.110577

Aspirin (acetylsalicylic acid) and clopidogrel are two major antithrombogenic agents that are widely used for the treatment and prevention of cerebro- and cardiovascular conditions such as stroke. Combined use produces enhanced therapeutic effect. Aspirin and clopidogrel both are esters, and hydrolysis leads to decreased or inactivated therapeutic activity. The aim of the study was to determine whether aspirin and clopidogrel are hydrolyzed by the same enzyme(s), thus reciprocally prolonging the antithrombogenic activity. To test this possibility, microsomes from the liver and intestine were assayed for the hydrolysis of aspirin and clopidogrel. In contrary to the hypothesis, aspirin and clopidogrel were hydrolyzed in a tissue-differential manner. Liver microsomes hydrolyzed both drugs, whereas intestinal microsomes hydrolyzed aspirin only. Consistent with the tissue distribution of two carboxylesterases human carboxylesterase (HCE) 1 and HCE2, recombinant HCE1 hydrolyzed clopidogrel, whereas recombinant HCE2 hydrolyzed aspirin. In addition, hydrolysis of clopidogrel among liver samples was correlated well with the level of HCE1, and hydrolysis of aspirin with HCE2. Certain natural variants differed from the wild-type enzymes on the hydrolysis of aspirin or clopidogrel. In the presence of ethyl alcohol, clopidogrel is converted to ethyl clopidogrel. Carboxylesterases are important pharmacological determinants for drugs containing ester linkages and exhibit a large interindividual variation. The isoform-specific hydrolysis of aspirin and clopidogrel suggests that these two antithrombogenic agents may have pharmacokinetic interactions with different sets of ester drugs, and the altered hydrolysis by polymorphic mutants provides a molecular explanation to the interindividual variation.