THE EFFECT OF HEPATIC-DISEASE ON THE DISPOSITION OF MORICIZINE IN HUMANS

The pharmacokinetics of moricizine and two of its metabolites, moriciz ine sulfoxide and phenothiazine-2-carbamic acid ethyl ester sulfoxide, were studied in healthy control subjects and in patients with chronic liver disease (cirrhosis). Moricizine disposition was significantly a ltered by hepatic cirrhosis. Compared to healthy subjects, the hepatic disease patients had an increased C-max (59%), an increased t(1/2) (1 41%), and a reduced plasma clearance (71%). Additionally, small but st atistically significant increases were observed for t(max) and the fra ction of moricizine not bound to plasma proteins in patients with hepa tic disease. The elimination of both moricizine metabolites was also a ltered by hepatic dysfunction as indicated by significantly prolonged terminal half-lives. Furthermore, there was a reduction in the convers ion of moricizine to moricizine sulfoxide. Both hepatic blood flow and hepatic metabolizing capacity were assessed in all subjects and patie nts by administration of indocyanine green and antipyrine, respectivel y. Indocyanine green and antipyrine plasma clearances were decreased b y 38 and 51%, respectively, indicating that both functions were dimini shed by hepatic cirrhosis. We conclude that the moricizine dose requir ed for arrhythmia patients with hepatic disease should be lower, and p erhaps, the dosing frequency should be less than in patients with norm al liver function.