title: Effect of the CYP2C8 genotype on the pharmacokinetics and pharmacodynamics of repaglinide.
abstract: The pharmacokinetics of repaglinide shows pronounced interindividual variability, for which several reasons have been considered, including interactions with drugs inhibiting CYP2C8 and CYP2C8 genetic polymorphism. However, existing data on the role of genetic polymorphisms in repaglinide disposition are not fully consistent. We studied the effect of CYP2C8*3 on the pharmacokinetics and pharmacodynamics of repaglinide in 29 healthy whites carrying CYP2C8*3/*3 (n = 4), CYP2C8*1/*3 (n = 13), or CYP2C8*1/*1 (n = 12). After administration of a single dose of 2 mg of repaglinide, blood was drawn for assessment of repaglinide pharmacokinetics and pharmacodynamics, and urine was collected to quantify the main repaglinide metabolites M1 and M4 up to 24 h postdose. Repaglinide and the metabolites were quantified by liquid chromatography-tandem mass spectrometry. Considering only the effect of CYP2C8*3, the mean (95% confidence interval) area under the time-concentration curve (AUC) from zero to infinity of repaglinide was 72.4 (6.7-138.0), 97.2 (59.2-135.2), and 105.9 (52.4-159.3) ng · ml(-1) · h and the maximal concentration (C(max)) was 38.5 (3.8-73.2), 50.3 (37.5-63.0), and 60.3 (31.5-89.1) ng · ml(-1), respectively, in carriers of CYP2C8*3/*3, CYP2C8*1/*3, and CYP2C8*1/*1 [p > 0.05, one-way analysis of variance (ANOVA)]. In addition, for urinary metabolite excretion and pharmacodynamic parameters, i.e., mean and maximal changes in insulin and glucose concentration, no significant differences between CYP2C8 genotypes were observed. Likewise, no significant effects on the pharmacokinetics or pharmacodynamics were observed when AUC and C(max) of repaglinide were corrected for reported effects of the SLCO1B1 521T>C polymorphism or when both polymorphisms were tested in a two-way ANOVA. In conclusion, CYP2C8*3 does not seem to play an important role in the pharmacokinetics and pharmacodynamics of repaglinide given in a therapeutic dose.
authors.affiliation: Department of Pharmacology, Clinical Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Köln, Germany. dorota.tomalik-scharte@uk-koeln.de
authors.forename: Dorota
authors.initials: D
authors.lastname: Tomalik-Scharte
authors.forename: Uwe
authors.initials: U
authors.lastname: Fuhr
authors.forename: Martin
authors.initials: M
authors.lastname: Hellmich
authors.forename: Dorothee
authors.initials: D
authors.lastname: Frank
authors.forename: Oxana
authors.initials: O
authors.lastname: Doroshyenko
authors.forename: Alexander
authors.initials: A
authors.lastname: Jetter
authors.forename: Julia C
authors.initials: JC
authors.lastname: Stingl
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D065727:Cytochrome P-450 CYP2C8; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D007328:Insulin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide
chemical_list: D001786:Blood Glucose; D002219:Carbamates; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; C072379:repaglinide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8