Title: CYP3A5 and CYP3A4 but not MDR1 Single-nucleotide Polymorphisms Determine Long-term Tacrolimus Disposition and Drug-related Nephrotoxicity in Renal Recipients
Authors: Kuypers, Dirk ×
de Jonge, Hylke
Naesens, Maarten
Lerut, Evelyne
Verbeke, Kristin
Vanrenterghem, Yves #
Issue Date: Dec-2007
Publisher: Mosby
Series Title: Clinical Pharmacology and Therapeutics vol:82 issue:6 pages:711-725
Abstract: 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 advance online publication 9 May 2007. doi:10.1038/sj.clpt.6100216.
ISSN: 0009-9236
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Nephrology
Translational Research in GastroIntestinal Disorders
Translational Cell & Tissue Research
Department of Microbiology & Immunology - miscellaneous
× corresponding author
# (joint) last author

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