Effect of SLCO1B1 genetic polymorphism on the pharmacokinetics of nateglinide.
OBJECTIVE
Nateglinide is a meglitinide analogue with antidiabetic action. A recent study showed that SLCO1B1 (which codes the OATP1B1 gene, also known as OATP-C, OATP2) is a major determinant which markedly affects the pharmacokinetics of repaglinide. Our objective was to assess the association between single nucleotide polymorphisms (SNPs) of SLCO1B1 and the pharmacokinetics of nateglinide.


METHODS
Seventeen healthy volunteers with different SLCO1B1 genotypes (11 with 521TT, four with 521TC and two with 521CC) were enrolled in this study. Each was given a single oral dose of 90 mg nateglinide. Plasma concentrations of nateglinide were measured up to 8 h by HPLC.


RESULTS
The C(max) and AUC(0,infinity) of nateglinide were 83% (P = 0.002) and 82% (P = 0.001) higher in the SLCO1B1521TC subjects (n = 4), and 76% (P = 0.016) and 108% (P = 0.001) higher in the SLCO1B1521CC subjects (n = 2) than in the SLCO1B1521TT subjects (n = 11), respectively. The t(1/2) of nateglinide in SLCO1B1521CC subjects was 78% longer than that in 521TT subjects (P = 0.036). The difference in t(max) values among the three genotypic groups was not statistically significant.


CONCLUSIONS
Our results suggest that OATP1B1-mediated hepatic uptake of nateglinide may be the prior step for its metabolism and elimination. SLCO1B1521T > C SNP might play an important role in the pharmacokinetics of nateglinide.
Zhang
Wei
W
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, PR China.
He
Yi-Jing
YJ
Han
Chun-Ting
CT
Liu
Zhao-Qian
ZQ
Li
Qing
Q
Fan
Lan
L
Tan
Zhi-Rong
ZR
Zhang
Wei-Xia
WX
Yu
Bang-Ning
BN
Wang
Dan
D
Hu
Dong-Li
DL
Zhou
Hong-Hao
HH
D000328:Adult; D003510:Cyclohexanes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D000077715:Nateglinide; D027361:Organic Anion Transporters / Q000235:genetics*; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D000077715:Nateglinide; D010649:Phenylalanine