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CYP2C19 genotype has a major influence on labetalol pharmacokinetics in healthy male Chinese subjects

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

Abstract

Purpose

The pharmacokinetics (PK) of labetalol show wide inter-subject variability, but the genetic causes for this are largely undetermined. This study was performed to examine whether common polymorphisms in UGT1A1, UGT2B7, CYP2C19 and ABCB1 affect the PK of labetalol.

Methods

The PK of labetalol were determined in 37 Chinese healthy male subjects who took a single oral dose of 200 mg labetalol. Plasma concentrations of labetalol were determined by a high-performance liquid chromatographic method. Subjects were genotyped for the CYP2C19*2 and *3, UGT1A1 *6, *28 and *60, UGT2B7*2 and ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms.

Results

Subjects with the CYP2C19*2/*2 genotype had a higher peak concentration (255.5 ± 80.1 vs. 156.0 ± 66.3 ng/mL; P < 0.05) and area under the concentration–time curve (AUC0−∞; 1,473.7 ± 493.6 vs. 502.8 ± 176.1 ng⋅h/mL; P < 0.001) than subjects with the *1/*1 genotype, and heterozygotes had intermediate values. The common UGT polymorphisms, UGT1A1*6, *60 or *28, and UGT2B7*2 did not result in a significant effect. Subjects with ABCB1 2677TA or TT or ABCB1 3435TT genotypes had higher AUC0−∞ and lower total clearance than the wild-types (P < 0.05), but this appeared to be related to the distribution of CYP2C19 genotypes. The CYP2C19 genotype appeared to be the only predictor of labetalol concentrations, accounting for approximately 60 % of the total variance in the AUC0−∞.

Conclusion

Our results suggest that the PK of labetalol are significantly affected by the common CYP2C19 polymorphisms in individuals of Chinese ethnicity. Future larger studies are needed to evaluate the effect of CYP2C19 and UGT1A1 polymorphisms on the PK of labetalol stereoisomers and the pharmacodynamic effects.

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Acknowledgments

We would like to thank the study volunteers for their participation and the other members of the research team who contributed to this study, especially Ms. Evelyn Chau and Ms. Swen Ip for the clinical study, Ms. Emily Poon for the genotyping and Ms. Sherry S. L. Lam for the drug assay.

Conflicts of interest/disclosure

The bioequivalence studies were supported by Vickmans Laboratories Limited, Hong Kong. The authors have no potential conflicts of interest with respect to this research.

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Author notes

  1. Ophelia Qi Ping Yin

    Present address: Novartis Pharmaceuticals Corporation, Florham Park, NJ, 07932, USA

  2. Moses Sing Sum Chow

    Present address: Center of Advancement of Drug Research and Evaluation, College of Pharmacy, Western University of Health Sciences, Pomona, CA, 91766-1854, USA

  3. Sze Wa Chan

    Present address: Department of Health Sciences, Caritas Institute of Higher Education, Tseung Kwan O, New Territories, Hong Kong

Authors and Affiliations

  1. Department of Medicine and Therapeutics, The Chinese University of Hong Kong–Prince of Wales Hospital, Shatin, New Territories, Hong Kong

    Sze Wa Chan, Miao Hu, Benny Siu Pong Fok & Brian Tomlinson

  2. Faculty of Medicine, Imperial College, London, UK

    Sara Shun Wah Ko

  3. Faculty of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland

    Catherine Wing Yan Tam

  4. School of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

    Ophelia Qi Ping Yin & Moses Sing Sum Chow

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  1. Sze Wa Chan
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Correspondence to Brian Tomlinson.

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Chan, S.W., Hu, M., Ko, S.S.W. et al. CYP2C19 genotype has a major influence on labetalol pharmacokinetics in healthy male Chinese subjects. Eur J Clin Pharmacol 69, 799–806 (2013). https://doi.org/10.1007/s00228-012-1428-x

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  • DOI: https://doi.org/10.1007/s00228-012-1428-x

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