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0091270007311569v1
48/3/311    most recent
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PHARMACOGENOMICS

Different Effects of SLCO1B1 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Repaglinide and Nateglinide

Annikka Kalliokoski, MD, Mikko Neuvonen, MSc, Pertti J. Neuvonen, MD and Mikko Niemi, MD

From the Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

Thirty-two healthy volunteers with different SLCO1B1 genotypes ingested a 0.5-mg dose of repaglinide and 60-mg dose of nateglinide with a washout period of 1 week. Participants with SLCO1B1 c.521CC genotype (n = 4) had a 59% (P = 0.001) or 72% (P < 0.001) greater mean area under the plasma repaglinide concentration-time curve (AUC0-{infty}) than participants with c.521TC (n = 12) or c.521TT (n = 16) genotypes. The AUC0-{infty} of repaglinide metabolites M2 and M4 were 112% (P = 0.004) and 81% (P = 0.002) larger in participants with c.521CC genotype than in those with c.521TT genotype, but no differences existed in the pharmacokinetics of M1. Maximum decrease in blood glucose concentration correlated with repaglinide AUC0-{infty} (r = 0.412, P = 0.019). SLCO1B1 polymorphism had no significant effect on the pharmacokinetics or pharmacodynamics of nateglinide or its M7 metabolite. Thus, in contrast to repaglinide, the disposition of nateglinide is unaffected by the SLCO1B1 c.521T>C polymorphism.

Key Words: Repaglinide • nateglinide • pharmacogenetics • OATP1B1 • SLCO1B1

Address for correspondence: Mikko Niemi, MD, Department of Clinical Pharmacology, Helsinki University Central Hospital, P.O. Box 340, FIN-00029 HUS, Finland; e-mail: mikko.niemi{at}helsinki.fi.


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