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Cyp3A4, Cyp3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients.

Abstract：

OBJECTIVE:The immunosuppressive drug tacrolimus requires strict therapeutic monitoring due to its narrow therapeutic index and great inter-individual variability. Cytochrome P450 3A4 (Cyp3A4) and Cyp3A5 are the most important contributors to tacrolimus metabolism while the P-glycoprotein pump (MDR-1) modulates its bioavailability. The objective was to investigate the association between Cyp3A4, Cyp3A5, and MDR-1 polymorphisms and tacrolimus pharmacokinetics in the early period after renal transplantation. METHODS:Forty-four renal transplant recipients were genotyped for 8 Cyp3A4, 7 Cyp3A5, and 5 MDR-1 genetic variants affecting the proteins' expression and/or function. Dose-adjusted tacrolimus though levels were determined during the first week after transplantation and correlated with corresponding genotype. RESULTS:We found no correlation between Cyp3A4 polymorphism and tacrolimus pharmacokinetics. Patients who do not carry both Cyp3A5*3 alleles achieved lower mean dose-adjusted tacrolimus blood concentrations (p<0.001) and needed a longer time to reach the target concentration (10-12 ng/ml; p<0.001) compared to Cyp3A5*3 homozygotes. Patients with less than three copies of MDR-1 (T-129C, C3435T and G2677T) polymorphisms, associated with reduced expression of P-glycoprotein, had also lower dose-adjusted tacrolimus blood concentrations compared to patients having equal to or greater than three copies of MDR-1 genetic variants (P=0.003). There was no difference in the rate of biopsy-confirmed acute rejection among groups during the first 3 months after transplantation. CONCLUSION:The complete absence of Cyp3A5*3 allele and the accumulation of less than three copies of MDR-1 (T-129C, C3435T and G2677T) polymorphisms are associated with lower tacrolimus blood levels identifying these genotypes as markers for patients requiring higher tacrolimus doses.

journal_name

Pharmacogenet Genomics

journal_title

Pharmacogenetics and genomics

authors

Roy JN,Barama A,Poirier C,Vinet B,Roger M

doi

10.1097/01.fpc.0000220571.20961.dd

subject

Has Abstract

pub_date

2006-09-01 00:00:00

pages

659-65

issue

eissn

1744-6872

issn

1744-6880

pii

01213011-200609000-00005

journal_volume

pub_type

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Cyp3A4, Cyp3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients.