title: Lack of tacrolimus circadian pharmacokinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipients.
abstract: OBJECTIVE
  We investigated whether tacrolimus pharmacokinetics shows circadian variation and the influence of the CYP3A5 A6986G polymorphism on the pharmacokinetics in both the early and maintenance stages after renal transplantation.
  
  
  METHODS
  Tacrolimus was administered twice daily at specified times (09.00 and 21.00 h) throughout the pre- and post-transplant period according to the trough-targeting strategy. Fifty recipients with stable graft function were studied on day 28 and beyond 1-year post transplantation. Whole blood samples were collected prior to and 1, 2, 3, 4, 6, 9 and 12 h after both the morning and evening doses during hospitalization.
  
  
  RESULTS
  Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage [AUC(0-12) 197.1 (95% confidence interval 182.9, 212.3) in daytime vs. 203.6 ng h ml(-1) (189.8, 217.4) in the night-time at day 28, 102.0 (92.1, 111.9) vs. 107.7 (97.9, 117.5) at 1 year, respectively]. In CYP3A5 *1 allele carriers (CYP3A5 expressers), body weight-adjusted oral clearance was markedly decreased from the early stage to the maintenance stage [0.622 (0.534, 0.709) to 0.369 l h(-1) kg(-1) (0.314, 0425)] compared with a smaller decrease [0.368 (0.305, 0.430) to 0.305 (0.217, 0.393)] in CYP3A5 non-expressers; however, the CYP3A5 genetic variation did not influence tacrolimus chronopharmacokinetics.
  
  
  CONCLUSIONS
  Equivalent daytime and night-time tacrolimus pharmacokinetics were achieved during both the early and maintenance stages with our specified-time administration strategy. The CYP3A5 polymorphism may be associated with the time-dependent changes in the oral clearance of tacrolimus, suggesting that genotyping of this polymorphism is useful for determining the appropriate dose of tacrolimus in both the early and maintenance stages after renal transplantation.
authors.affiliation: Department of Urology, Akita University School of Medicine, Hondo, Akita, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Satoh
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kagaya
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Inoue
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Inoue
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Numakura
authors.forename: Norihiko
authors.initials: N
authors.lastname: Tsuchiya
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tada
authors.forename: Toshio
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
mesh_terms: D019540:Area Under Curve; D002940:Circadian Rhythm / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D012150:Polymorphism, Restriction Fragment Length / Q000187:drug effects; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus