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 β- and α ₁ -adrenergic antagonist and (R)-(+)-carvedilol is only an α ₁ -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.
(© 2017, The American College of Clinical Pharmacology.)