Effects of clotrimazole on tacrolimus pharmacokinetics in patients with heart transplants with different CYP3A5 genotypes
- 155 Downloads
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.
KeywordsGenetic polymorphism CYP3A5 Tacrolimus Clotrimazole Drug interactions Transplantation
We would like to thank all the patients who participated in this study.
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
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.
This study was approved by the local ethic committee of the National Cerebral and Cardiovascular Center.
An informed consent was obtained from all individual participants included in the study.
- 6.Sattler M, Guengerich F, Yun C, Christians U, Sewing K (1992) Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos 20(5):753–761Google Scholar
- 9.Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins P, Daly A, Wrighton S, Hall S, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski M, Schuetz E (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27(4):383–391CrossRefGoogle Scholar
- 13.Nara M, Takahashi N, Miura M, Niioka T, Kagaya H, Fujishima N, Saitoh H, Kameoka Y, Tagawa H, Hirokawa M, Sawada K (2013) Effect of itraconazole on the concentrations of tacrolimus and cyclosporine in the blood of patients receiving allogeneic hematopoietic stem cell transplants. Eur J Clin Pharmacol 69(6):1321–1329CrossRefGoogle Scholar
- 14.Togashi M, Niioka T, Komatsuda A, Nara M, Okuyama S, Omokawa A, Abumiya M, Wakui H, Takahashi N, Miura M (2015) Effect of CYP3A5 and ABCB1 polymorphisms on the interaction between tacrolimus and itraconazole in patients with connective tissue disease. Eur J Clin Pharmacol 71(9):1091–1097CrossRefGoogle Scholar
- 16.Yamashita T, Fujishima N, Miura M, Niioka T, Abumiya M, Shinohara Y, Ubukawa K, Nara M, Fujishima M, Kameoka Y, Tagawa H, Hirokawa M, Takahashi N (2016) Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation. Cancer Chemother Pharmacol 78(1):111–118CrossRefGoogle Scholar
- 19.El-Asmar J, Gonzalez R, Bookout R, Mishra A, Kharfan-Dabaja MA (2016) Clotrimazole troches induce supratherapeutic blood levels of sirolimus and tacrolimus in an allogeneic hematopoietic cell-transplant recipient resulting in acute kidney injury. Hematol Oncol Stem Cell Ther 9(4):157–161CrossRefGoogle Scholar
- 21.Choy M (2010) Tacrolimus interaction with clotrimazole: a concise case report and literature review. P & T : a peer-Reviewed J Formulary Management 35(10):568–569Google Scholar
- 25.Cangemi G, Barco S, Bonifazio P, Maffia A, Agazzi A, Melioli G (2013) Comparison of antibody-conjugated magnetic immunoassay and liquid chromatography-tandem mass spectrometry for the measurement of cyclosporine and tacrolimus in whole blood. Int J Immunopathol Pharmacol 26(2):419–426CrossRefGoogle Scholar
- 33.Ohshima T, Miyakawa Y, Watanabe T, Ohyama K (2003) Effect of amphotericin B dilution with various beverages on the survival of Candida albicans cells. Kansenshōgaku zasshi J Japanese Assoc Infectious Diseases 77(1):29–33Google Scholar