title: Influence of SLCO1B3 genetic variations on tacrolimus pharmacokinetics in renal transplant recipients.
abstract: The immunosuppressive drug tacrolimus requires strict therapeutic monitoring due to its narrow therapeutic index and high interindividual variability. Organic anion transporting polypeptide 1B3 (OATP1B3) is a human hepatocyte transporter involved in the hepatobiliary elimination of diverse endogenous and exogenous substances. Genetic variations within the solute carrier (SLCO) 1B3 gene that encodes OATP1B3 may contribute to interindividual differences in tacrolimus disposition. The purpose of the present study is to investigate the association between SLCO1B3 polymorphisms and tacrolimus pharmacokinetics in renal transplant recipients. We found significant correlations between two linked coding nonsynomymous polymorphisms, T334G and G699A, and mean dose-adjusted tacrolimus trough blood concentrations during the first week post-transplantation (p = 0.04) and when the target dose (10-12 ng/ml) was obtained (p = 0.01). Patients carrying the homozygous mutant haplotype had 14.3-fold higher risk (95% confidence interval: 1.43-100; p = 0.02) of having blood tacrolimus concentrations above the median level, and thus being classified as poor OATP1B3 transporters, than carriers of one or two copies of the wild-type haplotype. This study shows, for the first time, that SLCO1B3 polymorphism is associated with tacrolimus exposure in the early post-transplant period.
authors.affiliation: Laboratoire d'Immunogénétique, Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Département de Microbiologie et Immunologie de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Andrée-Anne
authors.initials: AA
authors.lastname: Boivin
authors.forename: Héloïse
authors.initials: H
authors.lastname: Cardinal
authors.forename: Azemi
authors.initials: A
authors.lastname: Barama
authors.forename: Judith
authors.initials: J
authors.lastname: Naud
authors.forename: Vincent
authors.initials: V
authors.lastname: Pichette
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Hébert
authors.forename: Michel
authors.initials: M
authors.lastname: Roger
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016559:Tacrolimus