Lookup NU author(s): Julian Leathart,
Professor Ann Daly
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Objective: Our objective was to investigate the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C8 on the pharmacokinetics and pharmacodynamics of the meglitinide analog antidiabetic drug repaglinide. Methods: We genotyped 28 healthy volunteers who had participated in our pharmacokinetic studies on repaglinide for variant alleles of the CYP2C8. Each subject ingested a 0.25-mg dose of repaglinide, and plasma drug and blood glucose concentrations were monitored for 7 hours after dosing. Results: There were 19 subjects (68%) with the CYP2C8*1/*1 genotype (wild type), 6 subjects (21%) with the CYP2C8*1/*3 genotype, and 3 subjects (11%) with the CYP2C8*1/*4 genotype. In the 3 genotypic groups, the mean ± SD area under the plasma repaglinide concentration-time curve from time 0 to infinity [AUC(0-∞)] was 5.8 ± 2.5 ng · h/mL for CYP2C8*1/*1, 3.6 ± 0.9 ng · h/mL for CYP2C8*1/*3, and 5.1 ± 3.6 ng · h/mL for CYP2C8*1/*4. The mean AUC(0-∞) of repaglinide was 45% (P < .005) lower and the peak concentration in plasma was 39% lower (P < .05) in subjects with the CYP2C8*1/*3 genotype compared with those with the CYP2C8*1/*1 genotype. No statistically significant differences were found in the blood glucose response to repaglinide between the genotypes. Conclusions: Unexpectedly, the CYP2C8*3 variant allele was associated with reduced plasma concentrations of repaglinide. The effects of CYP2C8 polymorphisms on the pharmacokinetics of CYP2C8 substrates warrant further study.
Author(s): Niemi M, Leathart JB, Neuvonen M, Backman JT, Daly AK, Neuvonen PJ
Publication type: Article
Publication status: Published
Journal: Clinical Pharmacology and Therapeutics
ISSN (print): 0009-9236
ISSN (electronic): 1532-6535
Publisher: Nature Publishing Group
PubMed id: 14534525
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