No significant effect ofSLCO1B1polymorphism on the pharmacokinetics of rosiglitazone and pioglitazone

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Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• A common single nucleotide polymorphism (SNP) (c.521T→C) of theSLCO1B1gene, encoding the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1, has been associated with marked changes in the pharmacokinetics of the antidiabetic drug repaglinide.• Rosiglitazone and pioglitazone are competitive inhibitors of OATP1B1 and might thus be its substrates.• Gemfibrozil, an inhibitor of OATP1B1in vitro, considerably increases the plasma concentrations of rosiglitazone and pioglitazonein vivoin humans.WHAT THIS STUDY ADDS• TheSLCO1B1c.521T→C SNP was not associated with changes in rosiglitazone or pioglitazone pharmacokinetics in healthy volunteers.• OATP1B1 is thus unlikely to play an important role in the disposition of rosiglitazone or pioglitazone.AIMS: To examine possible effects of polymorphism in theSLCO1B1gene, encoding the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1, on the pharmacokinetics of rosiglitazone and pioglitazone in a prospective genotype panel study.METHODS: Sixteen healthy volunteers with the homozygousSLCO1B1c.521TT genotype (controls), 12 with the heterozygous c.521TC genotype and four with the homozygous c.521CC genotype ingested a single 4‐mg dose of rosiglitazone and a single 15‐mg dose of pioglitazone in a cross‐over study with a wash‐out period of at least 1 week.RESULTS: SLCO1B1polymorphism had no statistically significant effect on any of the pharmacokinetic variables of rosiglitazone, pioglitazone or their metabolites. The mean ± SD area under the plasma rosiglitazone concentration–time curve from time 0 to infinity (AUC0–∞) was 2024 ± 561 ng ml−1 h in the c.521TT subjects, 1763 ± 288 ng ml−1 h in the c.521TC subjects (geometric mean ratio c.521TC/c.521TT 0.89; 95% confidence interval 0.72, 1.11) and 1729 ± 346 ng ml−1 h in the c.521CC subjects (c.521CC/c.521TT 0.87; 0.63, 1.20). The AUC0–∞of pioglitazone averaged 6244 ± 1909 ng ml−1 h in the c.521TT subjects, 5123 ± 1165 ng ml−1 h in the c.521TC subjects (c.521TC/c.521TT 0.83; 0.65, 1.06) and 4851 ± 1123 ng ml−1 h in the c.521CC subjects (c.521CC/c.521TT 0.79; 0.55, 1.14). There was a significant correlation between the AUC0–∞of rosiglitazone and pioglitazone (r = 0.717,P < 0.001).CONCLUSIONS: TheSLCO1B1c.521T→C SNP does not affect the pharmacokinetics of rosiglitazone or pioglitazone, indicating that OATP1B1 plays no significant role in the disposition of these drugs.

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