Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide.
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.
Niemi
Mikko
M
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Leathart
Julian B
JB
Neuvonen
Mikko
M
Backman
Janne T
JT
Daly
Ann K
AK
Neuvonen
Pertti J
PJ
D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001786:Blood Glucose / Q000187:drug effects; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D016014:Linear Models; D008297:Male; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011110:Polymorphism, Genetic
D001786:Blood Glucose; D002219:Carbamates; D007004:Hypoglycemic Agents; D010880:Piperidines; C072379:repaglinide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8