Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers

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-m...

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Main Authors:	Aquilante, Christina L, Bushman, Lane R, Knutsen, Shannon D, Burt, Lauren E, Rome, Lucille Capo, Kosmiski, Lisa A
Format:	Online
Language:	English
Published:	BioMed Central 2008
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525178/

id	pubmed-3525178
recordtype	oai_dc
spelling	pubmed-35251782012-12-19 Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers Aquilante, Christina L Bushman, Lane R Knutsen, Shannon D Burt, Lauren E Rome, Lucille Capo Kosmiski, Lisa A Primary Research 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 CYP2C83 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 CYP2C81/*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; R2 = 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. BioMed Central 2008-09-01 /pmc/articles/PMC3525178/ /pubmed/19129086 http://dx.doi.org/10.1186/1479-7364-3-1-7 Text en Copyright ©2008 Henry Stewart Publications
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Aquilante, Christina L Bushman, Lane R Knutsen, Shannon D Burt, Lauren E Rome, Lucille Capo Kosmiski, Lisa A
spellingShingle	Aquilante, Christina L Bushman, Lane R Knutsen, Shannon D Burt, Lauren E Rome, Lucille Capo Kosmiski, Lisa A Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers
author_facet	Aquilante, Christina L Bushman, Lane R Knutsen, Shannon D Burt, Lauren E Rome, Lucille Capo Kosmiski, Lisa A
author_sort	Aquilante, Christina L
title	Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers
title_short	Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers
title_full	Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers
title_fullStr	Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers
title_full_unstemmed	Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers
title_sort	influence of slco1b1 and cyp2c8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers
description	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 CYP2C83 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 CYP2C81/*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; R2 = 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.
publisher	BioMed Central
publishDate	2008
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525178/
_version_	1611941286721355776

Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers

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