Hepatic drug clearance in patients with mild cystic fibrosis*

Abstract

The plasma disposition of three model substrates (lorazepam, indocyanine green, and antipyrine) and the formation clearance of antipyrine metabolites (3-hydroxymethylantipyrine, norantipyrine, and 4-hydroxyantipyrine) were evaluated in 15 subjects with mild cystic fibrosis and in 15 healthy control subjects. Plasma clearance was significantly greater in patients with cystic fibrosis for both lorazepam (1.7 +/- 0.4 versus 1.2 +/- 0.5 ml/min/kg) and indocyanine green (14.2 +/- 6.1 versus 9.1 +/- 3.0 ml/min/kg). In contrast, the clearance of antipyrine was not significantly different (1.0 +/- 0.7 versus 0.8 +/- 0.3 ml/min/kg), but the formation clearance for 3-hydroxymethylantipyrine was significantly greater in patients with cystic fibrosis. Lorazepam and antipyrine apparent steady-state volume of distribution were not different between groups. These results suggest that clearance of drugs that undergo conjugation (e.g., lorazepam) or biliary excretion (e.g., indocyanine green) is increased in patients with mild cystic fibrosis. In contrast, the increased formation clearance of only one antipyrine metabolite suggests that alterations in clearance of drugs metabolized by cytochrome P450 enzymes are substrate specific and isoform specific in patients with cystic fibrosis.

Disposition of acetaminophen and indocyanine green in cystic fibrosis-knockout mice

“…Homozygous female CF-mice showed an increased V when compared with the heterozygous mice used as controls (Table 3). These results are in agreement with previous reports of an increase in V for ICG in CF patients (3,4). Similar to CF patients, homozygous CF-mice also showed a trend towards lower peak concentrations of ICG relative to heterozygous mice (Table 3).…”

“…The disposition profile for ICG was best described by a 1-compartment model. This is similar to the human situation in which a 1-compartmental fit for ICG has been reported in CF patients (3,4). CF-knockout mice did not show any difference in total systemic clearance (CL), unlike the situation in CF patients, wherein increased clearance was reported to correlate with the severity of CF (2).…”

“…The mechanistic basis for the altered pharmacokinetics in CF is unknown, although alterations in hepatic metabolism, blood flow, or transport have been suggested (2)(3)(4). Determining a mechanism for altered pharmacokinetics of drugs in CF is unlikely if experimentation is limited to clinical studies.…”

“…Increased clearance of acetaminophen (APAP) and indocyanine green (ICG) has been reported in CF patients (2)(3)(4)(5). In order to test the above hypothesis, pharmacokinetics of 2 model compounds, APAP and ICG, were studied in CF-mice.…”

Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

“…Although the liver is the primary site of xenobiotic metabolism, the importance of the small intestine, which is a major site of drug absorption, is being increasingly recognized (31,43). In CF patients, metabolic clearance of some drugs has been reported to be increased (32,44,45), although those studies focused almost exclusively on hepatic clearance. Given the discrepancy between the downregulation of drug metabolism genes in the CF mouse intestine and the seemingly contradictory increase in drug clearance in CF patients, additional studies will be needed to understand the mechanisms underlying the changes in drug metabolism in CF and the relative roles of liver and intestinal xenobiotic metabolism.…”