title: 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, hCE1 and hCE2, are important mediators of drug metabolism. Both are expressed in the liver, but hCE1 greatly exceeds hCE2. In the intestine, only hCE2 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 hCE1 and hCE2 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.
authors: Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. claizure@uthsc.edu
authors: S Casey
authors: SC
authors: Laizure
authors: Vanessa
authors: V
authors: Herring
authors: Zheyi
authors: Z
authors: Hu
authors: Kevin
authors: K
authors: Witbrodt
authors: Robert B
authors: RB
authors: Parker
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000502:physiology; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000998:Antiviral Agents; D004364:Pharmaceutical Preparations; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D002265:Carboxylic Ester Hydrolases
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