Effect of Hepatic Disease on Drug Metabolism

Severe hepatic disease alters the metabolism of many drugs. Mild to moderate hepatic disease causes an unpredictable effect on drug clearance. Hepatic cytochrome

P450 enzyme activities and gene expression can be profoundly altered in disease states. In general, the levels of affected cytochrome P450 enzymes are depressed by diseases causing potential and documented impairment of drug clearance causing drug toxicity (73). In one study, it was reported that hepatocellular carcinoma decreased expression of CYP2E1 (74). Trotter et al. reported that total mean tacrolimus dose in year one after transplant was lower by 39% in patients with hepatitis C compared with that in patients with no hepatitis C infection. The most likely explanation for these findings is decreased hepatic clearance of tacrolimus caused by mild hepatic injury from recurrent hepatitis C virus (75). Zimmermann et al. reported that oral dose clearance of sirolimus (rapamycin) was significantly decreased in subjects with mild to moderate hepatic impairment compared with that in controls, and authors stressed the need for careful monitoring of trough whole blood sirolimus concentrations in renal transplant recipients exhibiting mild to moderate hepatic impairment (76).

The liver is responsible for producing albumin and other proteins, and hepatic impairment diminishes this process by decreasing concentrations of serum albumin and other proteins. Many drugs are bound to serum protein, and elevated concentration of strongly protein-bound drugs such as phenytoin and valproic acid in patients with hepatic impairment is well documented in the literature. Because free fraction of a drug is responsible for pharmacological action as well as toxicity monitoring, free drug concentrations and dose adjustment based on free drug levels is required in patients with liver disease. This issue is discussed in detail in Chapter 2.

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