Saturable Enantioselective First‐pass Effect for Carvedilol after High Oral Racemate Doses in Rats

Abstract

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.

Simultaneous quantification of carvedilol and its metabolites in rat plasma by ultra performance liquid chromatography tandem mass spectrometry and pharmacokinetic application

“…When CAR was given orally, the elimination halflife (t 1/2 ) usually varied between 3.1 and 18 h [17,[33][34][35][36][37]. In this study, the t 1/2 was 3.2 h after administration of a 1.5-1.8 mg doses for each rat in non-compartment model analysis, which is in good agreement with the reported value.…”

“…There are few reports on carvedilol pharmacokinetic study in rats [17,[33][34][35][36][37]. When CAR was given orally, the elimination halflife (t 1/2 ) usually varied between 3.1 and 18 h [17,[33][34][35][36][37].…”

Stereoselective glucuronidation of carvedilol by Chinese liver microsomes

“…The enantioselective pharmacokinetics of CARV has been widely investigated in rat, monkey, man and congestive heart failure (CHF) patients (Yang et al, 2004;Saito et al, 2006;Stahl et al, 1993;Fujimaki et al, 1990;Neugebauer et al, 1990). All results have led to the conclusion that (S)-enantiomer has greater intrinsic clearance in the liver.…”

Enantioselective pharmacokinetic–pharmacodynamic modelling of carvedilol in a NG-nitro-l-arginine methyl ester rat model of secondary hypertension

“…Linear pharmacokinetics of carvedilol has been described in elderly subjects after oral administration of 25–50 mg of the drug [31] . Conversely, a saturable first‐pass effect for carvedilol was found in rats after high oral racemate dosing [32] . Our results suggested that, after application of a single intravenous dose over the range of 1–5 mg/kg, both S ‐ and R ‐carvedilol showed a non‐linear pharmacokinetic pattern in control and L‐NAME treated rats, mainly as a consequence of an increased Vd ss .…”