Drug metabolism in liver disease.

The liver is the most important site of drug metabolism and patients with liver disease might be expected to have a reduced capacity to metabolize drugs. The rates of elimination of extensively metabolized drugs such as the barbiturates, diazepam, tolbutamide, isoniazid, phenylbutazone, rifampicin, lignocaine, paracetamol, aminopyrine, antipyrine and pethidine have been measured in patients with liver disease (Nelson, 1964; Levi, Sherlock, and Walker, 1968; Held and von Olderhausen, 1971; Prescott, Wright, Roscoe, and Brown, 1971; Mawer, Miller, and Turnberg, 1972; Branch, Herbert, and Read, 1973; Klotz, Avant, Wilkinson, Hoyumpa, and Schenker, 1973; Prescott and Stevenson, 1973; Thomson, Melmon, Richardson, Cohn, Steinbrunn, Cudihee, and Rowland, 1973; Adjepon-Yamoah, Nimmo, and Prescott, 1974; Hepner and Vesell, 1974; Hvidberg, Andreasen, and Ranek, 1974; Klotz, McHorse, Wilkinson, and Schenker, 1974). The results of these studies are conflicting, however, and it seems that many patients with chronic liver disease can metabolize drugs at a normal rate. In keeping with these observations, Schoene, Fleischmann, Remmer, and Olderhausen (1972) found that cytochrome P-450-activity and the demethylation rates of aminopyrine and p-nitroanisole in liver biopsy specimens from patients with liver disease were not reduced unless the patient had severe hepatitis or cirrhosis. Cytochrome-c-reductase activity was not reduced at all even in the most seriously damaged livers. On the other hand, drugmetabolizing enzyme activity was reduced in liver biopsies from patients with primary and secondary hepatic tumours (Pelkonen, Karki, and Larmi, 1973). Plasma cholinesterase is produced in the liver and the reduced activity of this enzyme in patients with liver disease is presumably due to impaired synthesis. Abnormally slow hydrolysis of drugs such as acetylsalicylic acid and procaine has been described in such patients (Reidenberg, James, and Dring, 1972). In contrast to the variable results observed in man, acute and chronic liver damage induced in experimental animals by agents such as carbon tetrachloride results in predictable and significant depression of drug metabolism (Dingell and Heimberg, 1968; Vorne and Arvela, 1971).