Enhanced hepatic drug clearance in patients with cystic fibrosis

To examine whether hepatic drug metabolism is altered in patients with cystic fibrosis (CF), we evaluated the pharmacokinetics of three model pharmacologic substrates (antipyrine, a marker of hepatic oxidative metabolism; lorazepam, a marker of hepatic glucuronosyltransferase activity; and indocyanine green (ICG), a marker of hepatic blood flow and biliary secretion) in 14 patients with CF (14.6 to 29.2 years of age) and in 12 children and adolescents with cancer (7.2 to 19.4 years of age), which was treated with only surgery and radiation. Each study subject received a single intravenous dose of the combined model substrates (0.03 mg/kg lorazepam, 10 mg/kg antipyrine, and 0.5 mg/kg ICG) for 5 minutes, followed by repeated blood sampling (n = 10) during a 24-hour postinfusion period. Patients with CF had a significantly greater plasma clearance of lorazepam (56.5 +/- 5.2 vs 25.9 +/- 1.9 ml/min/m2) and ICG (892.5 +/- 176.4 vs 256.5 +/- 41.7 ml/min/m2) but not of antipyrine (27.2 +/- 3.8 vs 20.7 +/- 2.0 ml/min/m2) in comparison with control subjects. The apparent steady-state volume of distribution for lorazepam, ICG, and antipyrine was significantly higher in the patients with CF (2.0-, 3.1-, and 1.4-fold, respectively) than in control subjects. Clearance of the model substrates did not correlate with standard biochemical markers of hepatic function. Similarly, no significant relationships were observed between the clearance or steady-state volume of distribution of the compounds and the National Institutes of Health prognostic scores for the patients with CF. These data demonstrate that the plasma clearance of lorazepam and ICG is increased in patients with CF and suggest that hepatic glucuronosyltransferase activity and biliary secretory capacity are enhanced in this disease.