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Pharmacogenomics. 2011 Sep;12(9):1281-91. doi: 10.2217/pgs.11.77. Epub 2011 Jul 19.

The P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients.

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

Abstract

AIM:

Recently a SNP of the gene encoding P450 oxidoreductase (POR*28; rs1057868C>T) has been associated with increased in vivo CYP3A activity using midazolam as a drug probe. Because tacrolimus is metabolized by CYP3A isoenzymes, this SNP might affect tacrolimus pharmacokinetics.

MATERIALS & METHODS:

To test this hypothesis we performed a study in a cohort of 298 de novo renal allograft recipients stratified according to CYP3A5 genotype, which has a known impact on tacrolimus pharmacokinetics.

RESULTS:

We found that in CYP3A5 expressers (CYP3A5*1 allele carriers) receiving a standard loading dose of 0.2 mg/kg, POR*28T allele carriers had lower tacrolimus C₀ levels in the first days post-transplantation and reached target C₀ levels significantly later as compared with POR*28CC homozygous patients. The POR*28T allele carriers had significantly higher tacrolimus dose requirements throughout the first year. In CYP3A5 nonexpressers (CYP3A5*3/*3) the POR*28 SNP did not affect tacrolimus pharmacokinetics.

CONCLUSION:

These data indicate that the POR*28 SNP is associated with additional increases in early tacrolimus dose-requirements in patients carrying a CYP3A5*1 allele.

PMID:
21770725
[PubMed - indexed for MEDLINE]
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