title: The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients.
abstract: Cyclosporine and tacrolimus are immunosuppressive drugs largely used in renal transplantation. They are characterized by a wide inter-individual variability in their pharmacokinetics with a potential impact on their therapeutic efficacy or induced toxicity. CYP3A5 and P-glycoprotein appear as important determinants of the metabolism of these drugs. The objective of this study was to investigate the effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood concentrations in stable transplant patients. Stable renal transplant recipients receiving cyclosporine (n = 50) or tacrolimus (n = 50) were genotyped for CYP3A5*3 and *6, and MDR1 C1236T, G2677T/A and C3435T. Dose-adjusted trough blood levels (ng/ml per mg/kg body weight) as well as doses (mg/kg body weight) required to achieve target blood concentrations were compared among patients according to allelic status for CYP3A5 and MDR1. Dose-adjusted trough concentrations were three-fold and 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1/*3 patients for tacrolimus and cyclosporine, respectively. In the case of tacrolimus, the difference was even more striking when considering CYP3A5*1/*1 patients showing dose-adjusted trough concentrations 5.8-fold lower than CYP3A5*3/*3 patients. For both drugs, no association was found between trough blood concentrations or dose requirement and MDR1 genotype. Multiple regression analyses showed that CYP3A5*1/*3 polymorphism explained up to 45% of the variability in dose requirement in relation to tacrolimus use. Given the importance of rapidly achieving target blood concentrations after transplantation, further prospective studies should consider the immediate post-graft period and assess the influence of this specific polymorphism. Beside non-genetic factors (e.g. steroids dosing, drugs interactions), CYP3A5 pharmacogenetic testing performed just before transplantation could contribute to a better individualization of immunosuppressive therapy.
authors.affiliation: Industrial and Environmental Toxicology Unit, Kidney and Pancreas Transplantation Unit, Clinical Chemistry Department, Université catholique de Louvain, St Luc Hospital, Brussels, Belgium. haufroid@toxi.ucl.ac.be
authors.forename: Vincent
authors.initials: V
authors.lastname: Haufroid
authors.forename: Michel
authors.initials: M
authors.lastname: Mourad
authors.forename: Valérie
authors.initials: V
authors.lastname: Van Kerckhove
authors.forename: Jeremie
authors.initials: J
authors.lastname: Wawrzyniak
authors.forename: Martine
authors.initials: M
authors.lastname: De Meyer
authors.forename: Djamila Chaib
authors.initials: DC
authors.lastname: Eddour
authors.forename: Jacques
authors.initials: J
authors.lastname: Malaise
authors.forename: Dominique
authors.initials: D
authors.lastname: Lison
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Squifflet
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallemacq
mesh_terms: D015331:Cohort Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D007166:Immunosuppressive Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016559:Tacrolimus; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C421109:multidrug resistance-associated protein 1