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 gene. 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- infinity )] 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- infinity ) 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.
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 gene. 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- infinity )] 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- infinity ) 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.
Authors: Julia Kirchheiner; Ivar Roots; Mark Goldammer; Bernd Rosenkranz; Jürgen Brockmöller Journal: Clin Pharmacokinet Date: 2005 Impact factor: 6.447
Authors: Rüdiger Kaspera; Suresh B Naraharisetti; Eric A Evangelista; Kristin D Marciante; Bruce M Psaty; Rheem A Totah Journal: Biochem Pharmacol Date: 2011-06-24 Impact factor: 5.858
Authors: Christina L Aquilante; Lisa A Kosmiski; David W A Bourne; Lane R Bushman; Elizabeth B Daily; Kyle P Hammond; Charles W Hopley; Rajendra S Kadam; Alexander T Kanack; Uday B Kompella; Merry Le; Julie A Predhomme; Joseph E Rower; Maha S Sidhom Journal: Br J Clin Pharmacol Date: 2013-01 Impact factor: 4.335