European Journal of Clinical Pharmacology

, Volume 75, Issue 1, pp 67–75 | Cite as

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

  • Takaya Uno
  • Kyoichi Wada
  • Sachi Matsuda
  • Yuka Terada
  • Nobue Terakawa
  • Akira Oita
  • Satoshi Yokoyama
  • Atsushi Kawase
  • Kouichi Hosomi
  • Mitsutaka TakadaEmail author
Pharmacokinetics and Disposition



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


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.


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.


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.


Genetic polymorphism CYP3A5 Tacrolimus Clotrimazole Drug interactions Transplantation 



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

Author 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

Funding information

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

Compliance with ethical standards

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.

Supplementary material

228_2018_2558_MOESM1_ESM.docx (108 kb)
ESM 1 (DOCX 107 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Takaya Uno
    • 1
    • 2
    • 3
  • Kyoichi Wada
    • 1
    • 3
  • Sachi Matsuda
    • 1
  • Yuka Terada
    • 1
    • 3
  • Nobue Terakawa
    • 1
  • Akira Oita
    • 1
  • Satoshi Yokoyama
    • 2
    • 3
  • Atsushi Kawase
    • 4
  • Kouichi Hosomi
    • 2
    • 3
  • Mitsutaka Takada
    • 2
    • 3
    Email author
  1. 1.Department of PharmacyNational Cerebral and Cardiovascular CenterSuitaJapan
  2. 2.Division of Clinical Drug Informatics, School of PharmacyKindai UniversityHigashi-osakaJapan
  3. 3.Division of Cardiovascular Drugs, TherapyKindai University Graduate School of PharmacyHigashi-osakaJapan
  4. 4.Department of Pharmacy, Faculty of PharmacyKindai UniversityHigashi-osakaJapan

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