Saturable enantioselective first-pass effect for carvedilol after high oral racemate doses in rats.
Carvedilol shows a highly enantioselective first-pass extraction after therapeutic p.o. doses with preferential extraction of the S-enantiomer. To investigate, whether the enantioselective first-pass metabolism is saturable, male Sprague-Dawley rats were administered increasing single doses of R/S-carvedilol (p.o., 5-30 mg/kg; i.v., 5 and 10 mg/kg), and the individual stereopharmacokinetics were studied. Like in humans the plasma concentrations of R-carvedilol exceeded always those of S-carvedilol. As expected, a dose-dependent reduction in oral clearance was observed, while the total clearance after the i.v. doses was constant. Beyond 20 mg/kg an increased plasma half-life was found for both enantiomers, which is due to a reduced plasma clearance.
Stahl
E
E
Pharmakologisches Institut für Naturwissenschaftler, Johann Wolfgang Goethe-Universität, Frankfurt/Main, Germany.
Henke
D
D
Mutschler
E
E
Spahn-Langguth
H
H
D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D002227:Carbazoles / Q000493:pharmacokinetics*; D000077261:Carvedilol; D008099:Liver / Q000378:metabolism; D008297:Male; D011412:Propanolamines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol