Hepatic Drug Metabolism in Cystic Fibrosis: Recent Developments and Future Directions

Abstract

OBJECTIVE: To review the most current information pertaining to hepatic drug metabolism in patients with cystic fibrosis (CF) and to explore the possible association between CF and specific pathways for the hepatic biotransformation of xenobiotics. DATA SOURCES: A MEDLINE search (key terms: cystic fibrosis, pharmacokinetics, metabolism, pharmacogenetics) was used to identify pertinent literature, including reviews. Research findings from the author's laboratory are also presented. STUDY SELECTION: Only recently reported (from 1988 to present), controlled, clinical investigations of hepatic drug metabolism in patients with CF are included. These investigations examined a mechanistic basis for altered drug biotransformation. Although uncontrolled clinical trials, case reports, and review articles are not included in the discussion, appropriate reference citations are made to these works. DATA EXTRACTION: Data from well-designed, controlled, clinical and basic investigations of altered hepatic drug biotransformation in patients with CF are summarized and discussed. New data from an ongoing study concerning the renal excretion of antipyrine metabolites in these patients are presented. DATA SYNTHESIS: In vivo studies of the formation clearance for metabolites of fleroxacin, sulfamethoxazole, and theophylline clearly demonstrate increased activity for important P-450 isoenzymes. These data are supported by an in vitro study that confirmed increased microsomal metabolism of theophylline to 1-methylxanthine, 3-methylxanthine, and 1,3-dimethyluric acid in a liver specimen from a patient with CF. These findings not only substantiate disease-specific increases in hepatic phase I biotransformation in patients with CF, but also verify the premise of substrate specificity for this pharmacogenetic phenomenon. Likewise, pharmacokinetic studies of drugs that undergo significant hepatic phase II biotransformation (e.g., furosemide, lorazepam, ibuprofen) appear to support increased hepatic drug clearance in patients with CF. This assertion has also been confirmed by a study of acetaminophen disposition, which demonstrated significantly increased formation clearance of the sulfate and glucuronide conjugates of the drug. Finally, the marked increase in the plasma clearance of indocyanine green, a pharmacologic probe for the biliary uptake and excretion of drugs, lends credence to the assertion that increased hepatic clearance of drugs in the presence of CF may be the consequence of disease-specific changes in both enzyme activity and/or drug transport within the liver. CONCLUSIONS: Investigations of drug biotransformation in CF have revealed disease-specific increases in the formation of drug metabolites. Future application of techniques in molecular biology and biochemical pharmacology will need to characterize the mechanistic basis for altered drug metabolism in CF and expand our knowledge of the relationship between drug metabolism phenotype and genotype; the impact of growth, development, and disease severity on drug metabolism; the potential role of CF gene products (i.e., CFTR) on intrahepatic drug transport and biotransformation; and the pharmacogenetic determinants of substrate specificity for hepatic drug metabolism in CF.