I)isposition of drugs in cystic hbrosis. VI. In vivo activitv of cvtochrome P450 isoforms involved i n thi 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 @)-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 @)-warfarin as a single intravenous bolus dose (0.375 mglkg), and urine and plasma samples were collected for 192 hours. The concentration of @-warfarin in plasma and the concentra- tion of @)-warfarin and its metabolites in urine were determined by HPLC and GCIMS, respectively. Plasma protein binding of @) -warfarin was measured by ultrafiltration. Results: The unbound plasma clearance of @)-warfarin was not significantly (p > 0.05) different be- tween the cystic fibrosis and the control groups (cystic fibrosis, 997 + 483 mYhr/kg; control, 788 +- 219 &/kg). The unbound metabolic clearances of @)-warfarin to its oxidative metabolites-6-h~- droxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin, and 10-hydroxywarfarin (mediated by P450 3A4)-were also similar @ > 0.05) in the two groups (6-hydrqwafarin: cystic fibrosis: 124.2 + 72.8 ml/hr/kg, control: 99.4 + 37.3 &/kg; 7-hydraxywafarin: cystic fibrosis: 43.8 + 32.2 &/kg, con- trol: 34.5 + 10.6 &/kg; 8-hydrqwafarin: cystic fibrosis: 80.4 + 85.4 &/kg, control: 69.5 +. 39.5 &/kg; 10-hydraxywafarin: cystic fibrosis: 4.38 2 2.72 &/kg, control: 16.28 + 13.71 &r/kg). Cml~ion: The in vivo activity of cytochrome P450 isoforms involved in the metabolism of @)-war- farin, including P450 3A4, is not enhanced in cystic fibrosis. (CLIN PHARMACOL THER 1994;55:528-34.) Ji-Ping Wang, MS, Jashvant D. Unadkat, PhD, Sharon McNamara, MN, Teresa A. OYSullivan, PharmD, Arnold L. Smith, MD, William F. Trager, PhD, and Bonnie Ramsey, MD Seattle, ~arh. Cystic fibrosis is the most common inherited, lethal disorder in the white population. Many of the clinical manifestations of cystic fibrosis, including chronic air- way infection with obstruction, pancreatic insuffi- ciency, and liver dysfunction, are a result of the vis- From the Departments of Pharmaceutics, Medicinal Chemistry, and Pediatrics, University of Washington, and Children's Hospital and Medical Center. Supported by grant NIHPSO DK 41978 and in part by grant NIHRR-37 from the National Institutes of Health. Received for publication Aug. 2, 1993; accepted Nov. 29, 1993. Reprint requests: Jashvant D. Unadkat, PhD, Department of Phar- maceutics, BG-20, University of Washington, Seattle, WA 98195. Copyright O 1994 by Mosby-Year Book, Inc. 0009-9236/94/$3 .OO + 0 1311153189 cous, dehydrated secretions of these organs caused by chloride impermeability across epithelial cell mem- branes.' The cystic fibrosis gene codes for a mem- brane protein, the cystic fibrosis transmembrane con- ductance regulator, which functions as a cyclic adenosine monophosphate-dependent chloride chan- ne12 and may also have other physiologic functions. At present, not all abnormalities in cystic fibrosis can be explained by the defect in chloride channel per- meability. For example, the mechanism(s) responsible for enhanced clearance of a variety of drugs in persons with cystic fibrosis3 is not well understood. To eluci- date the mechanistic basis of this phenomenon, our laboratory has conducted a series of in vivo experi- ments, using drugs as probes, to determine drug clear- ance pathways affected in cystic fibrosis. We have