Following cimetidine administration, 60% of the dose is excreted as unchanged drug in the urine, and 40% is eliminated by metabolism. We evaluated the effect of liver disease on cimetidine disposition by comparing its kinetics in 7 healthy subjects and 8 patients with alcoholic cirrhosis. Cirrhotic patients had severe liver disease as evidenced by the presence of ascites, hepatic encephalopathy, jaundice, muscle wasting, and low serum albumin, but serum creatinine and creatinine clearance did not differ significantly between controls and cirrhotics. Following intravenous administration, cimetidine systemic clearance was decreased by 56% in cirrhotics. This reduction was due in major part to an impairment of the renal clearance of unchanged drug. The ratio of cimetidine to creatinine clearance was 3.71 f 0.63 in controls, indicating active tubular secretion, and was decreased in cirrhotics (1.22 It 0.09, p c 0.05). The volume of distribution of cimetidine was also decreased by 39% in cirrhotics. To verify whether these findings observed after a single dose could be extended to patients receiving chronic cimetidine treatment, cimetidine trough (predose) plasma levels were measured in an additional group of 56 subjects receiving continuous cimetidine therapy (15 controls and 4 1 cirrhotics). Trough plasma levels did not differ significantly in controls and patients with compensated liver disease, but were elevated in patients with moderate and severe hepatic dysfunction. It is concluded that cimetidine clearance is decreased in patients with severe liver disease, mostly due to an impairment of the tubular secretion of unchanged drug, and that a reduction of cimetidine dosage is warranted in these patients, even in the presence of a normal creatinine clearance.
Cimetidine is widely used in the treatment of peptic ulcer disease, esophagitis, and gastritis, all of which are common in cirrhotic patients. Suppression of gastric acid production is dose-related, but central nervous system toxicity due to cimetidine is also dose-related and occurs most frequently in subjects with impaired renal or liver function (1, 2, Nouel, 0. et al., Gastroenterology 1980; 79:780-781, Correspondence).
In normal subjects, about 60% of an intravenous dose of cimetidine is excreted in the urine as unchanged drug and 40% by metabolism, presumably hepatic (3-6). Cimetidine sulfoxide has been identified as a major metabolite (3). In patients with renal failure, cimetidine elimination is clearly impaired (4-7), and reductions of the daily dose of cimetidine have been recommended (8). In