Vol. 26, Issue 10, 958-969, October 1998

Metabolism of Carvedilol in Dogs, Rats, and Mice

William H. Schaefer, James Politowski, Bruce Hwang, Frank Dixon, Jr., Anne Goalwin, Louis Gutzait, Kathleen Anderson,¹ Charles DeBrosse, Mark Bean, and Gerald R. Rhodes²

Departments of Drug Metabolism and Pharmacokinetics (W.H.S., J.P., B.H., F.D., A.G., L.G., K.A., G.R.R.), Analytical Chemistry (C.D.), and Structural and Physical Chemistry (M.B.), SmithKline Beecham Pharmaceuticals

The excretion and biotransformation of carvedilol [1-[carbazolyl-(4)-oxy]-3-[(2-methoxyphenoxyethyl)amino]-2-propanol], a new, multiple-action, neurohormonal antagonist that exhibits the combined pharmacological activities of -adrenoreceptor antagonism, vasodilation, and antioxidation, were investigated in dogs, rats, and mice. Carvedilol was absorbed well, and biliary secretion was predominant in each species. Carvedilol was metabolized extensively in each species, and elimination of unchanged compound was minor in bile duct-catheterized rats and dogs. In dogs, glucuronidation of the parent compound and hydroxylation of the carbazolyl ring, with subsequent glucuronidation, were the major metabolic pathways. Rats showed the simplest metabolite profile; the primary metabolites were formed by hydroxylation of the carbazolyl ring, with subsequent glucuronidation. Mice displayed the most complicated metabolite profile; glucuronidation of the parent compound and hydroxylation of either the carbazolyl or phenyl ring, with subsequent glucuronidation, were the major metabolic routes. O-Dealkylation was a minor pathway in all species examined.