Enhanced metabolism of
theophylline in subjects with
cystic fibrosis suggests that the activity of certain
cytochrome P450 isoforms is affected in subjects with this
genetic disease. To determine whether this effect on the
P450 enzymes is selective, the in vivo activity of the
cytochrome P450 isoform CYP2C9 was determined in adult subjects with
cystic fibrosis (n = 6) and in control subjects (n = 8). Subjects were administered (S)-
warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 96 hours. Plasma (S)-
warfarin concentrations were determined by HPLC; urinary concentrations of (S)-
warfarin and its metabolites were determined by gas chromatography-mass spectrometry. The total plasma clearance of (S)-
warfarin (subjects with
cystic fibrosis, 3.6 +/- 0.48 ml/hr/kg; control subjects, 3.82 +/- 0.73 ml/hr/kg), elimination half-life (subjects with
cystic fibrosis, 29.5 +/- 4.2 hours; control subjects, 25.9 +/- 5.4 hours); and steady-state volume of distribution (subjects with
cystic fibrosis, 153 +/- 18 ml/kg; control subjects, 138 +/- 22 ml/kg) were similar in the two groups (p > 0.05). The metabolic clearance of (S)-
warfarin to its major metabolites mediated by
CYP2C9,
6-hydroxywarfarin and
7-hydroxywarfarin, was not significantly (p > 0.05) different between the two groups (6-hydroxywarfarin: subjects with
cystic fibrosis, 0.33 +/- 0.1 ml/hr/kg; control subjects, 0.41 +/- 0.1 ml/hr/kg; 7-hydroxywarfarin: subjects with
cystic fibrosis, 1.34 +/- 0.49 ml/hr/kg; control subjects, 1.8 +/- 0.45 ml/hr/kg). On the basis of these data, we conclude that the in vivo
cytochrome P450 activity is selectively affected in persons with
cystic fibrosis.