title: Disposition of drugs in cystic fibrosis. VI. In vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin (including P450 3A4) is not enhanced in cystic fibrosis.
abstract: OBJECTIVE
  To determine whether the activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin is enhanced in cystic fibrosis.
  
  
  METHODS
  Six adult subjects with cystic fibrosis and six healthy control subjects, matched by age and sex, were administered (R)-warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 192 hours. The concentration of (R)-warfarin in plasma and the concentration of (R)-warfarin and its metabolites in urine were determined by HPLC and GC/MS, respectively. Plasma protein binding of (R)-warfarin was measured by ultrafiltration.
  
  
  RESULTS
  The unbound plasma clearance of (R)-warfarin was not significantly (p > 0.05) different between the cystic fibrosis and the control groups (cystic fibrosis, 997 +/- 483 ml/hr/kg; control, 788 +/- 219 ml/hr/kg). The unbound metabolic clearances of (R)-warfarin to its oxidative metabolites--6-hydroxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin, and 10-hydroxywarfarin (mediated by P450 3A4)--were also similar (p > 0.05) in the two groups (6-hydroxywarfarin: cystic fibrosis: 124.2 +/- 72.8 ml/hr/kg, control: 99.4 +/- 37.3 ml/hr/kg; 7-hydroxywarfarin: cystic fibrosis: 43.8 +/- 32.2 ml/hr/kg, control: 34.5 +/- 10.6 ml/hr/kg; 8-hydroxywarfarin: cystic fibrosis: 80.4 +/- 85.4 ml/hr/kg, control: 69.5 +/- 39.5 ml/hr/kg; 10-hydroxywarfarin: cystic fibrosis: 4.38 +/- 2.72 ml/hr/kg, control: 16.28 +/- 13.71 ml/hr/kg).
  
  
  CONCLUSIONS
  The in vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin, including P450 3A4, is not enhanced in cystic fibrosis.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle 98195.
authors.forename: J P
authors.initials: JP
authors.lastname: Wang
authors.forename: J D
authors.initials: JD
authors.lastname: Unadkat
authors.forename: S
authors.initials: S
authors.lastname: McNamara
authors.forename: T A
authors.initials: TA
authors.lastname: O'Sullivan
authors.forename: A L
authors.initials: AL
authors.lastname: Smith
authors.forename: W F
authors.initials: WF
authors.lastname: Trager
authors.forename: B
authors.initials: B
authors.lastname: Ramsey
mesh_terms: D000328:Adult; D001798:Blood Proteins / Q000378:metabolism; D003550:Cystic Fibrosis / Q000201:enzymology / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D011485:Protein Binding; D013237:Stereoisomerism; D014859:Warfarin / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D001798:Blood Proteins; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System