title: Combinational Effect of CYP3A5 and MDR-1 Polymorphisms on Tacrolimus Pharmacokinetics in Liver Transplant Patients.
abstract: OBJECTIVE
  Previous studies have reported reduced tacrolimus dose-adjusted exposure in individuals expressing the CYP3A5*1 allele (reference single nucleotide polymorphism identification number 776746). However, results on patients from South America are scarce. The objective of this study was to investigate the influence of CYP3A5 and MDR1 allelic variants and their correlation on the pharmacokinetics of tacrolimus and a modified release formulation of tacrolimus in stable patients with liver transplant.
  
  
  METHODS
  This was a prospective, single center, open-label study. Included patients were ≥ 18 years old and receiving a stable dose of tacrolimus for at least 6 months. Patients receiving stable treatment of twice daily tacrolimus were switched to a once-daily dose of modified release tacrolimus, on a milligram-to-milligram basis, with the modified release formulation administered for at least 4 weeks. Blood levels of tacrolimus were obtained before and 1 month after treatment was switched to the modified release formulation.
  
  
  RESULTS
  The frequency of the intron 3 allelic variant of the CYP3A5 isoform (G-to-A substitution at nucleotide 6986) in recipients was 16.6% and 25% in donors. Dose levels of tacrolimus and the modified formulation were significantly higher in donors and recipients who expressed CYP3A5 versus donors and recipients who did not express this allele. In addition, patients who received a liver from a donor expressing CYP3A5 had significantly lower trough concentrations of tacrolimus and the modified formulation. CYP3A5 expression in the donor liver affected tacrolimus (40.46%, P = .001) and modified formulation (37.56%, P = .001) variability. No association was found between the ABCB1 genotype and levels of tacrolimus or its modified formulation.
  
  
  CONCLUSIONS
  Our data suggest that CYP3A5*1 in either the donor or recipient resulted in higher mean daily doses of tacrolimus or its modified formulation to achieve target drug exposure in liver transplant patients.
authors.affiliation: Grupo de Investigación en Farmacología y Toxicología (INFARTO), Centro de Información y Estudio de Medicamentos y Tóxicos (CIEMTO), University of Antioquia, Colombia.
authors.forename: Jefferson Antonio
authors.initials: JA
authors.lastname: Buendía
authors.forename: Esteban
authors.initials: E
authors.lastname: Otamendi
authors.forename: María Cecilia
authors.initials: MC
authors.lastname: Kravetz
authors.forename: Fernando
authors.initials: F
authors.lastname: Cairo
authors.forename: Andrés
authors.initials: A
authors.lastname: Ruf
authors.forename: María
authors.initials: M
authors.lastname: de Davila
authors.forename: Yanina
authors.initials: Y
authors.lastname: Powazniak
authors.forename: Julieta
authors.initials: J
authors.lastname: Nafissi
authors.forename: Alberto
authors.initials: A
authors.lastname: Lazarowski
authors.forename: Guillermo
authors.initials: G
authors.lastname: Bramuglia
authors.forename: Federico
authors.initials: F
authors.lastname: Villamil
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D001118:Argentina; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus