Carvedilol

Abstract

Carvedilol is a nonselective β‐blocker/α‐blocker used in the treatment of mild to moderate congestive heart failure. The in vitro metabolism of carvedilol was investigated in dog, rat, and human liver microsomes, human intestinal microsomes, as well as recombinant human cytochrome P450, and UDP‐glucuronosyltransferases. O‐Demethylation and aryl hydroxylation were major metabolic reactions, which were catalyzed by CYP2C9, 2D6, 1A2, 3A4, and 2E1. O‐Glucuronidation was catalyzed mainly by UGT1A1, 2B4, and 2B7. The metabolism of [ 14 C]‐carvedilol was studied in healthy male volunteers after a single oral dose of 50 mg. The mean total radioactivity recovered in urine represented 82% of the administered dose. Carvedilol was extensively metabolized and the unchanged drug in urine accounted for <2% of the dose. N ‐Glucuronide conjugate at the nitrogen of the carbazol substructure was identified as the major metabolite. Other minor metabolic reactions observed include oxidative ether cleavage of side chain, O‐demethylation, O‐glucuronide/sulfate conjugation, and aryl hydroxylation.