title: Drug interaction of (S)-warfarin, and not (R)-warfarin, with itraconazole in a hematopoietic stem cell transplant recipient.
abstract: BACKGROUND
  Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein, but not CYP2C9. Herein, we report a case study in which the plasma concentration of the CYP2C9 substrate (S)-warfarin, and not the CYP3A4 substrate (R)-warfarin, increased with itraconazole coadministration.
  
  
  METHODS
  A 67-y-old man received an allogenic bone marrow transplant for acute lymphoid leukemia. He was taking oral itraconazole (200mg/day) and was started on a warfarin dose of 2.0mg/day. The plasma concentrations of (S)- and (R)-warfarin 3 days after starting warfarin administration were 216 and 556 ng/mL, respectively (INR 0.98), and after 10 days, the concentrations were 763 and 545 ng/mL, respectively (INR 2.43). On day 11 after withdrawal of itraconazole, the concentrations of (S)- and (R)-warfarin were 341 and 605ng/mL, respectively (INR 1.38). The concentration of (R)-warfarin was not affected by itraconazole; however, the final (S)-warfarin concentration had increased 7.3-fold. The (S)-warfarin/(S)-7-hydroxywarfarin ratio decreased to 2.45 from 8.40 after discontinuation of itraconazole. The permeability of warfarin enantiomers across Caco-2 cells was not influenced by itraconazole and showed no difference between enantiomers.
  
  
  CONCLUSIONS
  Careful INR monitoring is necessary for warfarin co-administration with itraconazole. Further examination is necessary to elucidate mechanisms of the interaction between warfarin and itraconazole.
authors.affiliation: Department of Pharmacy, Akita University Hospital, Akita, Japan. m-miura@hos.akita-u.ac.jp
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
authors.forename: Naoto
authors.initials: N
authors.lastname: Takahashi
authors.forename: Syu-ichi
authors.initials: S
authors.lastname: Kanno
authors.forename: Shoutaro
authors.initials: S
authors.lastname: Kato
authors.forename: Miho
authors.initials: M
authors.lastname: Nara
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Itoh
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Saitoh
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kameoka
authors.forename: Naohito
authors.initials: N
authors.lastname: Fujishima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tagawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirokawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sawada
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000097:blood; D016026:Bone Marrow Transplantation; D018938:Caco-2 Cells; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000628:therapy*; D013237:Stereoisomerism; D014184:Transplantation, Homologous; D014859:Warfarin / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry
chemical_list: D017964:Itraconazole; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases