Abstract
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 β-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.
Footnotes
-
Send reprint requests to: William H. Schaefer, Merck and Co., WP45-325, West Point, PA 19486.
-
↵1 Current address: ThermoQuest Finnigan Corp., San Jose, CA 95134.
-
↵2 Current address: Rhône Poulenc Rorer, Department of Drug Disposition, Collegeville, PA 19426.
- Abbreviations used are::
- FAB
- fast atom bombardment
- CID
- collisionally induced dissociation
- NOE
- nuclear Overhauser enhancement
- DMSO
- dimethylsulfoxide
- COSY
- correlated spectroscopy
- UDPGA
- UDP-glucuronic acid
- Received December 8, 1997.
- Accepted May 25, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|