The Role of Human Carboxylesterases in Drug Metabolism: Have We Overlooked Their Importance?

Abstract

Carboxylesterases are a multigene family of mammalian enzymes widely distributed throughout the body that catalyze the hydrolysis of esters, amides, thioesters, and carbamates. In humans, two carboxylesterases, hCE 1 and hCE 2, are important mediators of drug metabolism. Both are expressed in the liver, but hCE 1 greatly exceeds hCE 2. In the intestine, only hCE 2 is present and highly expressed. The most common drug substrates of these enzymes are ester prodrugs specifically designed to enhance oral bioavailability by hydrolysis to the active carboxylic acid after absorption from the gastrointestinal tract. Carboxylesterases also play an important role in the hydrolysis of some drugs to inactive metabolites. It has been widely believed that drugs undergoing hydrolysis by hCE 1 and hCE 2 are not subject to clinically significant alterations in their disposition, but evidence exists that genetic polymorphisms, drug‐drug interactions, drug‐disease interactions and other factors are important determinants of the variability in the therapeutic response to carboxylesterase‐substrate drugs. The implications for drug therapy are far‐reaching, as substrate drugs include numerous examples from widely prescribed therapeutic classes. Representative drugs include angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, antiplatelet drugs, statins, antivirals, and central nervous system agents. As research interest increases in the carboxylesterases, evidence is accumulating of their important role in drug metabolism and, therefore, the outcomes of pharmacotherapy.