title: Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers.
abstract: Polymorphisms in drug transporter genes and/or drug-metabolising enzyme genes may contribute to inter-individual variability in rosiglitazone pharmacokinetics in humans. We sought to determine the joint effects of polymorphisms in the SLCO1B1 drug transporter gene and the cytochrome P450 ( CYP ) 2C8-metabolising enzyme gene on rosiglitazone pharmacokinetics in healthy volunteers. Healthy Caucasian subjects were prospectively enrolled on the basis of SLCO1B1 521 T > C genotype. Additionally, subjects were genotyped for SLCO1B1 -11187 G > A, -10499 A > C and 388 A > G polymorphisms, and the CYP2C8*3 polymorphism. SLCO1B1 haplotypes and diplotypes were computationally assigned. Rosiglitazone plasma concentrations were determined by high-performance liquid chromatography and analysed using non-compartmental methods. The study population consisted of 26 subjects, with a mean age of 33 +/- 9 years, and a mean weight of 66.6 +/- 11.7 kg. There were no significant differences in rosiglitazone pharmacokinetic parameters between SLCO1B1 diplotype groups. Subjects with the CYP2C8*1/*3 genotype ( n = 7), however, had significantly lower rosiglitazone area under the plasma concentration-time curve (AUC) and significantly higher rosiglitazone oral clearance, compared with CYP2C8 wild-type homozygotes ( n = 19). Stepwise linear regression analysis revealed that CYP2C8 genotype ( p = 0.006) and weight ( p = 0.022) were significant predictors of rosiglitazone AUC (overall p = 0.002; R 2 = 41.6 per cent). We concluded that polymorphisms in the CYP2C8 drug-metabolising enzyme gene, but not the SLCO1B1 drug transporter gene, significantly influence rosiglitazone disposition in humans. Future studies examining the influence of CYP2C8 genotypes and haplotypes on thiazolidinedione disposition and response in patients with type 2 diabetes are warranted.
authors.affiliation: University of Colorado at Denver School of Pharmacy, Department of Pharmaceutical Sciences, 4200 East Ninth Avenue, Denver, CO 80262, USA. Christina.aquilante@UCHSC.edu
authors.forename: Christina L
authors.initials: CL
authors.lastname: Aquilante
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.forename: Shannon D
authors.initials: SD
authors.lastname: Knutsen
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Burt
authors.forename: Lucille Capo
authors.initials: LC
authors.lastname: Rome
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Kosmiski
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D005838:Genotype; D006262:Health; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8