title: Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation.
abstract: BACKGROUND
  Tacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT).
  
  
  METHODS
  Twenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake.
  
  
  RESULTS
  Thirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele.
  
  
  CONCLUSIONS
  CYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan. naofuji@doc.med.akita-u.ac.jp.|Division of Blood Transfusion, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan. naofuji@doc.med.akita-u.ac.jp.
authors.forename: Naohito
authors.initials: N
authors.lastname: Fujishima
authors.affiliation: Department of Pharmacy, Akita University Hospital, Akita, Japan.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
authors.affiliation: Department of Pharmacy, Akita University Hospital, Akita, Japan.
authors.forename: Takenori
authors.initials: T
authors.lastname: Niioka
authors.affiliation: Department of Pharmacy, Akita University Hospital, Akita, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Abumiya
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Shinohara
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Ubukawa
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Nara
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Fujishima
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kameoka
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tagawa
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.|Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirokawa
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Takahashi
mesh_terms: D058186:Acute Kidney Injury / Q000453:epidemiology*; D000328:Adult; D000368:Aged; D000483:Alleles; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology; D001393:Azoles / Q000008:administration & dosage / Q000494:pharmacology; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: Azole antifungal agent; CYP3A5 polymorphism; Hematopoietic stem cell transplantation; Once-daily tacrolimus formulation; Pharmacokinetics