Drug Metabolism and Chronic Liver Disease

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DESCRIPTION (provided by applicant): This is a resubmission of a proposal whose goal is to use pharmacogenetic principles to better understand the influence of liver disease associated with hepatitis C on drug disposition and develop new tools to evaluate hepatic function. We propose to address the following specific hypotheses: In Specific Aim 1: Hepatitis C influences the clearance of drugs that undergo metabolism in comparison to matched controls. Furthermore, the extent of change in clearance is different for drugs that are metabolized by different drug metabolizing enzymes and is associated with the severity of the liver disease. Specific Aim 2: Selective decreases in drug metabolism in patients with hepatitis C without hepatic decompensation is associated with enzyme specific down-regulation of hepatic expression of mRNA for that enzyme and increased circulating levels of the cytokines, Interleukin-6 and Tumor Necrosis Factor- ?. Specific Aim 3: The measurement of activity of multiple drug metabolizing enzymes can be interpreted in the context of a sequential, progressive model of hepatic dysfunction to provide an integrated assessment of hepatic function and prognosis in patients with hepatitis C. We propose to study patients with hepatitis C (n= 112) associated with chronic persistent hepatitis, chronic active hepatitis and cirrhosis with or without hepatic decompensation and age, sex matched controls (n=48) on two occasions. Each study subject will participate in three pharmacokinetic (PK) studies that uses drugs selected as probes of substrates metabolized predominantly or exclusively by an individual drug metabolizing enzyme. Part 1: A cocktail to include: caffeine (CYP1A2), flurbiprofen (CYP2C9), mephenytoin (CYP2C19), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and dapsone (acetylation). Part 2: Semi-simultaneous oral:intravenous administration with midazolam to measure intestinal and hepatic contributions to CYP3A metabolism and Part 3: oral administration of acetaminophen (UGT1A6) simultaneously with intravenous morphine (UGT2B7). When feasible, liver tissue obtained at the time of diagnostic liver biopsy as part of routine patient care will have concentrations of mRNA for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, UGT1A6 and UGT2B7 measured. Patients with hepatitis C-associated liver disease will be followed at 6 monthly intervals until liver transplantation, death or duration of funding. The study will be repeated either after a change in clinical status or at 2 years in patients with liver disease and after one or 12 months in control subjects. Collectively, these studies will provide a consolidated base of information within the same cohort of patients with hepatitis C and normal subjects to better understand the influence of hepatitis C-associated live disease on drug metabolizing enzymes. This information has potential to create new integrated indices to evaluate hepatic function and prognosis.