title: Pharmaceutical and genetic determinants for interindividual differences of tacrolimus bioavailability in renal transplant recipients.
abstract: OBJECTIVE
  The pharmacokinetics of orally administered immediate-release, twice-daily (BID) and modified-release, once-daily (QD) formulations of tacrolimus have high interindividual variability. We investigated factors affecting interindividual variability of tacrolimus bioavailability in renal transplant patients.
  
  
  METHODS
  Ninety-seven Japanese renal transplant patients (47 patients on tacrolimus BID and 50 patients on tacrolimus QD) were enrolled in this study. The tacrolimus absolute bioavailability was calculated using the area under the concentration-time curve from 0 to 24 h (AUC0-24) after continuous intravenous infusion and oral formulations of tacrolimus in the same recipient.
  
  
  RESULTS
  The median (quartile 1-quartile 3) tacrolimus relative bioavailability for recipients with the CYP3A5*1 or CYP3A5*3/*3 alleles was significantly lower for the tacrolimus QD group [9.1 % (6.3-10.7 %) and 15.4 % (11.5-18.7 %), respectively] than for the tacrolimus BID group [12.6 % (9.9-14.2 %) and 19.3 % (16.5-24.8 %), respectively] (P = 0.004 and 0.028, respectively). Consequently, tacrolimus absolute bioavailability was lowest for recipients with the CYP3A5*1 allele taking tacrolimus QD. The CYP3A5 polymorphism had no impact on the dose-adjusted AUC0-24 of tacrolimus in patients on continuous intravenous infusion (P = 0.906).
  
  
  CONCLUSIONS
  The larger interindividual variability of tacrolimus bioavailability for oral formulations appears to be due to the effects of the CYP3A5 polymorphism and the tacrolimus oral formulation. These factors should therefore be taken into account when determining individualized tacrolimus dosing.
authors.affiliation: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Takenori
authors.initials: T
authors.lastname: Niioka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kagaya
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Numakura
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Inoue
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Satoh
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus