title: Effect of CYP3A5 and ABCB1 polymorphisms on the interaction between tacrolimus and itraconazole in patients with connective tissue disease.
abstract: OBJECTIVE
  The aim of this study was to investigate the effect of itraconazole (ITCZ), a potent inhibitor of CYP3A4 and P-glycoprotein, on the blood concentration 12 h after tacrolimus administration (C 12h) in relation to CYP3A5 6986A>G and ABCB1 3435C>T genotype status in patients with connective tissue disease (CTD).
  
  
  METHODS
  Eighty-one CTD patients taking tacrolimus (Prograf®) once daily at night (2100 hours) were enrolled in this study. Whole blood samples were collected 12 h after tacrolimus administration at steady state.
  
  
  RESULTS
  The dose-adjusted tacrolimus C 12h with or without ITCZ co-administration was significantly higher in patients with CYP3A5*3/*3 than in those with the CYP3A5*1 allele [CYP3A5 *1/*1 vs. *1/*3 vs. *3/*3 = 1.67 vs. 2.70 vs. 4.83 ng/mL/mg (P = 0.003) and 0.68 vs. 0.97 vs. 2.20 ng/mL/mg (P < 0.001), respectively], but differences were not observed for ABCB1 genotypes. However, there was no difference in the increase rate of the dose-adjusted C 12h of tacrolimus between CYP3A5 or ABCB1 genotypes (P = 0.378 and 0.259). On the other hand, reduction of the estimated glomerular filtration rate exhibited a correlation with the C 12h of tacrolimus after ITCZ co-administration (r = -0.482, P = 0.009).
  
  
  CONCLUSIONS
  In CYP3A5*3/*3 patients, because the metabolic pathway for tacrolimus occurs only through CYP3A4, the combination with ITCZ seems to lead to a higher risk of acute renal dysfunction. Therefore, we suggest that the target blood tacrolimus concentration be set as low as possible through dose-adjustment for patients with the CYP3A5*3/*3 allele.
authors.affiliation: Department of Hematology, Nephrology, Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Togashi
authors.forename: Takenori
authors.initials: T
authors.lastname: Niioka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Komatsuda
authors.forename: Mizuho
authors.initials: M
authors.lastname: Nara
authors.forename: Shin
authors.initials: S
authors.lastname: Okuyama
authors.forename: Ayumi
authors.initials: A
authors.lastname: Omokawa
authors.forename: Maiko
authors.initials: M
authors.lastname: Abumiya
authors.forename: Hideki
authors.initials: H
authors.lastname: Wakui
authors.forename: Naoto
authors.initials: N
authors.lastname: Takahashi
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D003240:Connective Tissue Diseases / Q000188:drug therapy / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D065692:Cytochrome P-450 CYP3A Inhibitors; D007166:Immunosuppressive Agents; D017964:Itraconazole; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus