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Effects of clotrimazole on tacrolimus pharmacokinetics in patients with heart transplants with different CYP3A5 genotypes

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

Abstract

Purpose

This study aimed to investigate the effects of clotrimazole on the pharmacokinetics of tacrolimus in Japanese patients with heart transplants with different CYP3A5 genotypes.

Methods

Twenty-six patients who underwent heart transplantation between June 2012 and July 2017 were enrolled in this retrospective study. The CYP3A5 (rs776746; CYP3A5*3) genotype was determined after monitoring and analysing tacrolimus blood concentrations. The pharmacokinetic profile of tacrolimus was examined before and after the discontinuation of clotrimazole and in patients with different CYP3A5 genotypes.

Results

The CYP3A5*1/*1, *1/*3 and *3/*3 genotypes were detected in 2, 8 and 16 patients, respectively. After clotrimazole was discontinued, the CYP3A5 expresser (CYP3A5*1/*1 or *1/*3) group had a 3.3-fold median increase in apparent oral clearance of tacrolimus (0.27 vs. 0.89 L/h/kg, P = 0.002) compared with the CYP3A5 non-expresser (CYP3A5*3/*3) group with a 2.2-fold median increase (0.18 vs. 0.39 L/h/kg, P < 0.0001). Significant correlations were observed between C0 and area under the concentration–time curve (AUC0–12) of tacrolimus after the discontinuation of clotrimazole in the CYP3A5 expresser and non-expresser groups, respectively (R2 = 0.49 and 0.42, all P < 0.05), but not before the discontinuation of clotrimazole.

Conclusion

The effects of clotrimazole on tacrolimus pharmacokinetics in the CYP3A5 expresser patients were significantly greater than those in the CYP3A5 non-expresser patients. In addition, clotrimazole disturbed the correlation between C0 and AUC0–12 of tacrolimus. Careful dose adjustment of tacrolimus based on CYP3A5 genotypes may be beneficial for the patients with heart transplants who are concomitantly treated with clotrimazole.

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Acknowledgements

We would like to thank all the patients who participated in this study.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Pharmacy, National Cerebral and Cardiovascular Center, Suita, Japan

    Takaya Uno, Kyoichi Wada, Sachi Matsuda, Yuka Terada, Nobue Terakawa & Akira Oita

  2. Division of Clinical Drug Informatics, School of Pharmacy, Kindai University, 3-4-1, Kowakae, Higashi-osaka, Osaka, 577-8502, Japan

    Takaya Uno, Satoshi Yokoyama, Kouichi Hosomi & Mitsutaka Takada

  3. Division of Cardiovascular Drugs, Therapy, Kindai University Graduate School of Pharmacy, Higashi-osaka, Japan

    Takaya Uno, Kyoichi Wada, Yuka Terada, Satoshi Yokoyama, Kouichi Hosomi & Mitsutaka Takada

  4. Department of Pharmacy, Faculty of Pharmacy, Kindai University, Higashi-osaka, Japan

    Atsushi Kawase

Authors
  1. Takaya Uno
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  2. Kyoichi Wada
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  10. Mitsutaka Takada
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Contributions

Participated in research design: Uno, Wada, Matsuda, Terada and Takada

Conducted experiments and clinical study: Uno, Wada, Matsuda, Terada and Takada

Performed data analysis: Uno, Wada, Kawase and Takada

Wrote or contributed to the writing of the manuscript: Uno, Wada, Terakawa, Oita, Kawase, Yokoyama, Hosomi and Takada

Corresponding author

Correspondence to Mitsutaka Takada.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This study was approved by the local ethic committee of the National Cerebral and Cardiovascular Center.

Informed consent

An informed consent was obtained from all individual participants included in the study.

Additional information

This study was conducted in the Department of Pharmacy, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, Japan.

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Uno, T., Wada, K., Matsuda, S. et al. Effects of clotrimazole on tacrolimus pharmacokinetics in patients with heart transplants with different CYP3A5 genotypes. Eur J Clin Pharmacol 75, 67–75 (2019). https://doi.org/10.1007/s00228-018-2558-6

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  • DOI: https://doi.org/10.1007/s00228-018-2558-6

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