title: Effect of ABCB1 diplotype on tacrolimus disposition in renal recipients depends on CYP3A5 and CYP3A4 genotype.
abstract: The relevance of most genetic polymorphisms beyond CYP3A5*1 on tacrolimus disposition remains unclear. We constructed a predictive mixed model for tacrolimus dose-corrected trough concentration (C0/dose) at months 3, 12 and 24 after transplantation in a retrospective cohort of 766 predominantly Causasian adult renal recipients (n=2042 trough concentrations). All patients were genotyped for 32 single-nucleotide polymorphisms with a proven or possible relevance to tacrolimus disposition based on the previous studies. Of these, ABCB1, ABCC2, OATP1B1, COMT, FMO, PPARA and APOA5 were analyzed as (functional) diplotype groups. Predictors of C0/dose were CYP3A5*1, hematocrit, age, CYP3A4*22, use of concomitant CYP3A4 inhibitor or inducer, ALT, estimated glomerular filtration rate, tacrolimus formulation (once vs twice daily), ABCB1 diplotype and time after transplantation. The effect of ABCB1 diplotype was small but strongly accentuated in CYP3A4*22 carriers and non-existent in CYP3A5 expressors. ABCC2 diplotype had a limited effect on C0/dose that was only statistically significant in CYP3A5 non-expressors.
authors.affiliation: Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven, Belgium.|Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Vanhove
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: P
authors.identifier: 0000-0003-3525-7351
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Department of Oncology, Laboratory for Translational Genetics, KU Leuven-University of Leuven, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven, Belgium.|Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: D R J
authors.initials: DRJ
authors.lastname: Kuypers
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus