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

Objective To determine whether the activity of cytochrome P450 isoforms involved in the metabolism of (R) ‐warfarin is enhanced in cystic fibrosis. Design 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‐hy‐droxywarfarin, 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‐hydroxywafarin : cystic fibrosis: 4.38 ± 2.72 ml/hr/kg, control: 16.28 ± 13.71 ml/hr/kg). Conclusion The in vivo activity of cytochrome P450 isoforms involved in the metabolism of (R) ‐warfarin, including P450 3A4, is not enhanced in cystic fibrosis. Clinical Pharmacology and Therapeutics (1994) 55, 528–534; doi: 10.1038/clpt.1994.66