Population pharmacokinetics of carvedilol enantiomers and their metabolites in healthy subjects and type-2 diabetes patients.

Carvedilol, a drug available as a racemic mixture, is metabolised into hydroxyphenylcarvedilol (OHC) by CYP2D6 and O-desmethylcarvedilol (DMC) by CYP2C9 followed by conjugation to glucuronides. In contrast to other ß-adrenergic receptor antagonists, carvedilol does not induce insulin resistance or worsen glycaemic control in diabetic hypertensive patients. This study aims to investigate the implications of type 2 diabetes (T2DM) on the pharmacokinetics of carvedilol enantiomers using an integrated population pharmacokinetic modelling approach. In total, 14 T2DM patients with good glycaemic control receiving standard doses of metformin and glibenclamide were evaluated along with a control group of 13 healthy subjects. Serial blood samples were collected up to 24h after administration of a single 25mg dose of racemic carvedilol. A multicompartmental population pharmacokinetic model describing the enantioselective disposition of the parent compound, OHC and DMC was developed in NONMEM v7.2. Even though data are limited, it appears that despite inhibition of CYP2C9 due to long-term glibenclamide administration to T2DM patients, overall no differences are observed in the total clearance of carvedilol when compared to healthy subjects (43.1 vs. 45.9L/h for (S)-(-)-carvedilol and 29.0 vs. 33.1L/h for (R)-(+)-carvedilol). These results provide evidence of a compensatory mechanism for the inhibition of CYP2C9, with higher contribution of CYP2D6 activity to the elimination of carvedilol. Consequently, no dose adjustment is recommended for carvedilol in T2DM patients receiving glibenclamide and metformin.

Effects of Type 2 Diabetes Mellitus in Patients on Treatment With Glibenclamide and Metformin on Carvedilol Enantiomers Metabolism.

Carvedilol is available in clinical practice as a racemate in which (S)-(-)-carvedilol is a ß- and α1 -adrenergic antagonist and (R)-(+)-carvedilol is only an α1 -adrenergic antagonist. Carvedilol is mainly metabolized by glucuronidation, by CYP2D6 to hydroxyphenylcarvedilol (OHC), and by CYP2C9 to O-desmethylcarvedilol (DMC). This study evaluated the pharmacokinetics of carvedilol enantiomers and their metabolites OHC and DMC in healthy volunteers (n = 13) and in type 2 diabetes mellitus patients with good glycemic control (n = 13). The healthy subjects were enrolled to receive either a 25-mg oral single dose of carvedilol alone (no DDI) or carvedilol simultaneously with 5 mg glibenclamide and 500 mg metformin (DDI), whereas type 2 diabetes mellitus patients who were on long-term treatment with glibenclamide (5 mg/8 h) and metformin (500 mg/8 h) were enrolled to receive only a single oral dose of 25 mg carvedilol. The plasma concentrations of the (R)-(+)-carvedilol, (R)-(+)-DMC, and (R)-(+)-OHC were higher than those of (S)-(-)-carvedilol, (S)-(-)-DMC, and (S)-(-)-OHC in all investigated groups. The pharmacokinetics of the carvedilol enantiomers did not differ between the groups. However, the AUC values of the DMC enantiomers were lower in the type 2 diabetes mellitus patients than in the healthy volunteers (DDI and no DDI) [(R)-(+), 6.9, 10.4, 11.9 ng·h/mL; and (S)-(-), 2.4, 4.3, 4.0 ng·h/mL, respectively]. In contrast, the AUC values of the OHC enantiomers were higher in the type 2 diabetes mellitus patients [(R)-(+), 13.9, 6.6, 4.9 ng·h/mL; and (S)-(-), 7.2, 1.5, 1.5 ng·h/mL], which explains the fact that the carvedilol pharmacokinetics was unchanged.