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Effects of SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of repaglinide in healthy Chinese volunteers

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Repaglinide is commonly used in the treatment of patients with type 2 diabetes mellitus to reduce postprandial hyperglycemia. The objective of this research was to study the effects of SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of repaglinide in healthy Chinese volunteers.

Methods

A total of 22 healthy young male participants were recruited from a pool of pharmacogenetically characterized participants genotyped for SLCO1B1, CYP3A4, and CYP2C8 SNPs by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Volunteers with CYP2C8*3 and CYP3A4*4 alleles were excluded from the clinical study. Then selected volunteers took part in the clinical pharmacokinetic study, receiving 2 mg repaglinide.

Results

Healthy participants with SLCO1B1*1A/*1B or *1A/*1A genotype and SLCO1B1 *15/*1A or *5/*1A genotype had significantly higher AUC0-∞ than participants with SLCO1B1*1B/*1B genotype, with the former showing an increase over the latter of 39.81 and 42.09%, respectively (P = 0.028, 0.032). The clearance in the former two genotype groups was significantly attenuated (by 27.39 and 28.55%, respectively) compared with individuals with SLCO1B1*1B/*1B genotype (P = 0.015, 0.019). No significant differences in blood glucose-lowering effect were observed among three genotype groups.

Conclusions

SLCO1B1*1B/*1B genotype is associated with reduced pharmacokinetic exposure after a single dose oral administration of 2 mg repaglinide, including decreased AUC0-∞ and increased clearance of repaglinide. Moreover, this polymorphism of SLCO1B1 has significant influence on the pharmacokinetics of repaglinide, but no effects on its pharmacodynamics.

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Abbreviations

SLCO1B1 :

The encoding gene of the human organic anion-transporting polypeptides OATP1B1

CYP2C8 :

Cytochrome P-450 2C8 gene

CYP3A4 :

Cytochrome P-450 3A4 gene

SNPs:

Single nucleotide polymorphisms

Cmax :

Peak plasma concentration

AUC0-8 :

Area under plasma concentration-time curve from 0 to 8 h

AUC0-∞ :

Area under plasma concentration-time curve from 0 to infinity

Tmax :

Time to Cmax

T1/2 :

Elimination half-life

CL:

Clearance

AAC0-3h :

Area above blood glucose level-time curve from 0 to 3 h

NS:

Nonsignificant

T2D:

Type 2 diabetes

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Acknowledgments

The study was supported by the 863 Hi-tech Program of China (No. 2007AA02Z171).

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Authors and Affiliations

  1. Center for Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Mailbox 210, #24 Tongjiaxiang, Nanjing, Jiangsu, 210009, People’s Republic of China

    Jiake He, Zhixia Qiu, Ning Li, Yang Lu, Deen Han, Tingting Li, Di Zhao, Wei Sun, Fang Fang, Jianheng Zheng & Xijing Chen

  2. Bioanalysis Service, WuXi AppTec Co. Ltd, Shanghai, 200131, People’s Republic of China

    Yang Yu

  3. Clinical Pharmacology Laboratory, Nanjing First Hospital Affiliated to Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu, 210006, People’s Republic of China

    Hongwei Fan

Authors
  1. Jiake He
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  2. Zhixia Qiu
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  4. Yang Yu
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  5. Yang Lu
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  10. Fang Fang
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  13. Xijing Chen
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Correspondence to Hongwei Fan or Xijing Chen.

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He, J., Qiu, Z., Li, N. et al. Effects of SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of repaglinide in healthy Chinese volunteers. Eur J Clin Pharmacol 67, 701–707 (2011). https://doi.org/10.1007/s00228-011-0994-7

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  • DOI: https://doi.org/10.1007/s00228-011-0994-7

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