Effect of theCYP2C8Genotype on the Pharmacokinetics and Pharmacodynamics of Repaglinide
Autor: | D Frank, Julia C. Stingl, Oxana Doroshyenko, Dorota Tomalik-Scharte, Martin Hellmich, Uwe Fuhr, Alexander Jetter |
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Rok vydání: | 2011 |
Předmět: |
Adult
Blood Glucose Male Genotype Metabolite Pharmaceutical Science Urine Pharmacology Polymorphism Single Nucleotide Cytochrome P-450 CYP2C8 Excretion chemistry.chemical_compound Piperidines Pharmacokinetics medicine Humans Hypoglycemic Agents Insulin Drug Interactions CYP2C8 biology Middle Aged Repaglinide chemistry Pharmacodynamics biology.protein Female Aryl Hydrocarbon Hydroxylases Carbamates SLCO1B1 medicine.drug |
Zdroj: | Drug Metabolism and Disposition. 39:927-932 |
ISSN: | 1521-009X 0090-9556 |
Popis: | 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. |
Databáze: | OpenAIRE |
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