CYP3A5 and CYP3A4 but not MDR1 Single‐nucleotide Polymorphisms Determine Long‐term Tacrolimus Disposition and Drug‐related Nephrotoxicity in Renal Recipients

The impact of CYP3A and MDR1 gene single‐nucleotide polymorphisms on long‐term tacrolimus disposition and drug‐related toxicity has not been assessed. A study was performed in 95 genotyped recipients by measuring (12 and 4 h) concentration–time curves on day 7; 3, 6 months; 1, 2, 3, 4, and 5 years after transplantation. In contrast to recipients carrying the CYP3A4*1/CYP3A5*1 or CYP3A4*1B/CYP3A5*1 genotypes, dose‐corrected tacrolimus exposure almost doubled over 5 years in patients with the CYP3A4*1/ CYP3A5*3 genotype (AUC 0–12 h : from 41.7±18.7 to 80±39.2 ng h/ml/mg; P <0.05), whereas apparent oral steady‐state clearance and dose requirements significantly decreased accordingly. The CYP3A4*1/CYP3A5*1 and CYP3A4*1B/CYP3A5*1 genotypes were significantly more frequently associated with the development of biopsy‐proven tacrolimus‐related nephrotoxicity than the CYP3A4*1/ CYP3A5*3 genotype (37.5 vs 11.2%; P =0.03 and 42.8 vs 11.2%; P =0.02). The lack of a time‐related increase in dose‐corrected tacrolimus exposure observed with the CYP3A4*1/CYP3A5*1 and CYP3A4*1B/CYP3A5*1 genotypes is associated with tacrolimus‐related nephrotoxicity, possibly as a result of higher concentrations of toxic metabolites. Clinical Pharmacology & Therapeutics (2007) 82 , 711–725; doi: 10.1038/sj.clpt.6100216 ; published online 9 May 2007