Metabolism of carvedilol in dogs, rats, and mice.
The excretion and biotransformation of carvedilol [1-[carbazolyl-(4)-oxy]-3-[(2-methoxyphenoxyethyl)amino]-2-p ropanol], a new, multiple-action, neurohormonal antagonist that exhibits the combined pharmacological activities of beta-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.
Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, USA.
W H
WH
Schaefer
J
J
Politowski
B
B
Hwang
F
F
Dixon
A
A
Goalwin
L
L
Gutzait
K
K
Anderson
C
C
DeBrosse
M
M
Bean
G R
GR
Rhodes
D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000493:pharmacokinetics; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002227:Carbazoles / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D000077261:Carvedilol; D004285:Dogs; D005243:Feces / Q000737:chemistry; D006801:Humans; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D011412:Propanolamines / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000493:pharmacokinetics
D000319:Adrenergic beta-Antagonists; D000975:Antioxidants; D002227:Carbazoles; D002250:Carbon Radioisotopes; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol