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CYP3A5 and CYP3A4 but not MDR1 Single‐nucleotide Polymorphisms Determine Long‐term Tacrolimus Disposition and Drug‐related Nephrotoxicity in Renal Recipients
Author(s) -
Kuypers D R J,
Jonge H,
Naesens M,
Lerut E,
Verbeke K,
Vanrenterghem Y
Publication year - 2007
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100216
Subject(s) - tacrolimus , cyp3a4 , cyp3a5 , nephrotoxicity , genotype , pharmacology , pharmacokinetics , cyp3a , single nucleotide polymorphism , medicine , pharmacogenetics , transplantation , biology , gastroenterology , kidney , cytochrome p450 , genetics , gene , metabolism
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