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Pharmacogenomics. 2013 Sep;14(12):1467-80. doi: 10.2217/pgs.13.133.

Impact of CYP3A5 genotype on tacrolimus versus midazolam clearance in renal transplant recipients: new insights in CYP3A5-mediated drug metabolism.

Author information

1
Department of Nephrology & Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.

Abstract

BACKGROUND & AIM:

In vitro studies have identified both midazolam and tacrolimus as dual CYP3A4 and CYP3A5 substrates. In vivo; however, the CYP3A5 genotype has a marked impact on tacrolimus pharmacokinetics, whereas it seems not to affect midazolam pharmacokinetics. The aim of the current study was to explore this paradigm in a relevant clinical setting.

PATIENTS & METHODS:

A case-control study in 80 tacrolimus-treated renal transplant recipients comparing systemic and apparent oral midazolam clearance and tacrolimus pharmacokinetics in CYP3A5 expressers (CYP3A5*1 allele carriers) and CYP3A5 nonexpressers (CYP3A5*3/*3) was performed.

RESULTS:

CYP3A5 expressers display an approximately 2.4-fold higher tacrolimus clearance as compared with CYP3A5 nonexpressers, whereas there are no differences in systemic and apparent oral midazolam clearance.

CONCLUSION:

These data confirm that in vivo CYP3A5 plays an important role in tacrolimus metabolism, while its contribution to midazolam metabolism in a relevant study population is limited. Furthermore, these data suggest that midazolam is to be considered as a phenotypic probe for in vivo CYP3A4 activity rather than combined CYP3A4 and CYP3A5 activity.

PMID:
24024898
DOI:
10.2217/pgs.13.133
[Indexed for MEDLINE]

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