title: Effects of Type 2 Diabetes Mellitus in Patients on Treatment With Glibenclamide and Metformin on Carvedilol Enantiomers Metabolism.
abstract: Carvedilol is available in clinical practice as a racemate in which (S)-(-)-carvedilol is a β- 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.
authors.affiliation: Faculdade de Ciências Farmacêuticas Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Glauco H B
authors.initials: GHB
authors.lastname: Nardotto
authors.affiliation: Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Eduardo B
authors.initials: EB
authors.lastname: Coelho
authors.affiliation: Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Paiva
authors.affiliation: Faculdade de Ciências Farmacêuticas Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000328:Adult; D019540:Area Under Curve; D002227:Carbazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077261:Carvedilol; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D018737:Hand Strength / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008875:Middle Aged; D011412:Propanolamines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D007004:Hypoglycemic Agents; D011412:Propanolamines; D000077261:Carvedilol; D008687:Metformin; D005905:Glyburide
keywords: carvedilol; enantiomers; metabolism; pharmacokinetics; type 2 diabetes mellitus