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Effects of Type 2 Diabetes Mellitus in Patients on Treatment With Glibenclamide and Metformin on Carvedilol Enantiomers Metabolism
Author(s) -
Nardotto Glauco H. B.,
Coelho Eduardo B.,
Paiva Carlos E.,
Lanchote Vera L.
Publication year - 2017
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.864
Subject(s) - carvedilol , metformin , medicine , pharmacology , pharmacokinetics , glibenclamide , diabetes mellitus , type 2 diabetes mellitus , glycemic , type 2 diabetes , endocrinology , heart failure
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.