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First published on February 24, 2006; DOI: 10.1124/dmd.105.008680

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Received for publication December 1, 2005.
Revised February 14, 2006.
Accepted for publication February 14, 2006.

Effect of CYP3A5 Polymorphism on Tacrolimus Metabolic Clearance In Vitro

Yang Dai 1, Mary F. Hebert 1, Nina Isoherranen 1, Connie L. Davis 1, Christopher Marsh 1, Danny D. Shen 1, Kenneth E. Thummel 1*

1 University of Washington

* Address correspondence to: E-mail: thummel{at}u.washington.edu

Abstract

Previous investigations of solid organ transplant patients treated with tacrolimus showed that individuals carrying a CYP3A5*1 allele have lower dose adjusted trough blood concentrations compared to homozygous CYP3A5*3 individuals. The objective of this investigation was to quantify the contribution of CYP3A5 to the hepatic and renal metabolic clearance of tacrolimus. Four primary tacrolimus metabolites 13-DMT (major), 15-DMT, 31-DMT and 12-HT were generated by heterologously-expressed CYP3A4 and CYP3A5 and human liver microsomes. The total unbound intrinsic clearance of tacrolimus by CYP3A5 was twice that by CYP3A4 and, under non-saturating conditions, the formation rates of 13-DMT, 31-DMT and 12-HT were ≥ 1.7-fold higher, on average, in human liver microsomes with a CYP3A5*1/*3 genotype compared to those with a homozygous CYP3A5*3/*3 genotype. In addition, formation of 13-DMT was 13.5-fold higher in human kidney microsomes with a CYP3A5*1/*3 genotype compared to those with a CYP3A5*3/*3 genotype. These data suggest that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus in the liver and kidney.


Key words: liver microsomes, polymorphisms


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