title: Weight of ABCB1 and POR genes on oral tacrolimus exposure in CYP3A5 nonexpressor pediatric patients with stable kidney transplant.
abstract: Tacrolimus (TAC) is highly effective for the prevention of acute organ rejection. However, its clinical use may be challenging due to its large interindividual pharmacokinetic variability, which can be partially explained by genetic variations in TAC-metabolizing enzymes and transporters. The aim of this study was to evaluate the influence of genetic and clinical factors on TAC pharmacokinetic variability in 21 stable pediatric renal transplant patients. This study was nested in a previous Prograf to Advagraf conversion clinical trial. CYP3A5, ABCB1 and two POR genotypes were assessed by real-time PCR. The impact on TAC pharmacokinetics of individual genetic variants on CYP3A5 nonexpressors was evaluated by genetic score. Explicative models for TAC AUC0-24h,Cmaxand Cminafter Advagraf were developed by linear regression. The built genetic scores explain 13.7 and 26.5% of the total AUC0-24hand Cmintotal variability, respectively. Patients genetic information should be considered to monitorizate and predict TAC exposure.
authors.affiliation: Department of Clinical Pharmacology, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: G N
authors.initials: GN
authors.lastname: Almeida-Paulo
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM), La Paz University Hospital, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Dapía García
authors.affiliation: Department of Clinical Pharmacology, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Lubomirov
authors.affiliation: Department of Clinical Pharmacology, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: A M
authors.initials: AM
authors.lastname: Borobia
authors.affiliation: Department of Clinical Pharmacology, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: N L
authors.initials: NL
authors.lastname: Alonso-Sánchez
authors.affiliation: Department of Pediatric Nephrology, La Paz University Hospital, IdiPAZ, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Espinosa
authors.affiliation: Department of Clinical Pharmacology, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.
authors.forename: A J
authors.initials: AJ
authors.lastname: Carcas-Sansuán
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D002648:Child; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006084:Graft Rejection / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000379:methods; D008297:Male; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007166:Immunosuppressive Agents; C000602470:POR protein, human; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus