Influence of <it>SLCO1B1 </it>and <it>CYP2C8 </it>gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers

• Main Authors: Aquilante Christina L, Bushman Lane R, Knutsen Shannon D, Burt Lauren E, Rome Lucille Capo, Kosmiski Lisa A
• Format: Article
• Language: English
• Published: BMC 2008-09-01
• Series: Human Genomics
• Subjects: rosiglitazone; thiazolidinedione; pharmacokinetic; pharmacogenetic; CYP2C8; SLCO1B1
• Online Access: http://www.humgenomics.com/content/3/1/7
• ISSN: 1479-7364

<p>Abstract</p> <p>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 <it>SLCO1B1 </it>drug transporter gene and the cytochrome P450 (<it>CYP</it>) 2C8-metabolising enzyme gene on rosiglitazone pharmacokinetics in healthy volunteers. Healthy Caucasian subjects were prospectively enrolled on the basis of <it>SLCO1B1 </it>521 T > C genotype. Additionally, subjects were genotyped for <it>SLCO1B1 </it> 11187 G > A, - 10499 A > C and 388 A > G polymorphisms, and the <it>CYP2C8*3 </it>polymorphism. <it>SLCO1B1 </it>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 <it>SLCO1B1 </it>diplotype groups. Subjects with the <it>CYP2C8*1/*3 </it>genotype (<it>n </it>= 7), however, had significantly lower rosiglitazone area under the plasma concentration-time curve (AUC) and significantly higher rosiglitazone oral clearance, compared with <it>CYP2C8 </it>wild-type homozygotes (<it>n </it>= 19). Stepwise linear regression analysis revealed that <it>CYP2C8 </it>genotype (<it>p </it>= 0.006) and weight (<it>p </it>= 0.022) were significant predictors of rosiglitazone AUC (overall <it>p </it>= 0.002; <it>R</it>²= 41.6 per cent). We concluded that polymorphisms in the <it>CYP2C8 </it>drug-metabolising enzyme gene, but not the <it>SLCO1B1 </it>drug transporter gene, significantly influence rosiglitazone disposition in humans. Future studies examining the influence of <it>CYP2C8 </it>genotypes and haplotypes on thiazolidinedione disposition and response in patients with type 2 diabetes are warranted.</p>