Treatment of liver disease with malotilate. A pharmacokinetic and pharmacodynamic phase II study in cirrhosis.
Malotilate, a sulphur-containing compound with antifibrotic and hepatoprotective properties in several animal models, has been investigated in cirrhotic patients. Nine patients with cirrhosis of various aetiologies and severity, and 4 healthy volunteers, participated in a pharmacokinetic study. After a single dose of 500 mg malotilate p.o. peak malotilate plasma concentration measured by GC-MS was 35 times higher in patients (median 0.70 micrograms/ml) than in controls (median 0.019 micrograms/ml). The median apparent oral clearance was approximately 50 times lower in cirrhotics (median 2.21/min) than in healthy volunteers (1181/min). The apparent oral clearance was significantly correlated with indicators of portal-systemic shunting, such as the 2-h postprandial serum bile acids and the bioavailability of oral nitroglycerine. Urinary output of the glucuronidated metabolite-(M3), measured by HPLC, was normal in patients, whereas recovery of metabolite-M6 (resulting from ring opening and loss of sulphur) was reduced. Six patients in an open 6-month trial received malotilate 200 mg t.i.d. for 2 months and 400 mg t.i.d. for 4 months. The thrombocyte count increased and serum ferritin level fell in all patients, and serum cholinesterase rose and IgA decreased in 5 of 6. The other indicators of liver function did not show a significant change. Dry skin was the only possible adverse effect. It is concluded that first-pass elimination of malotilate is dramatically reduced in cirrhotics, and that a smaller amount of the drug reaches the liver in such patients. Malotilate was well tolerated, even in patients with advanced disease.
D000328:Adult; D001682:Biological Availability; D001711:Biotransformation; D002908:Chronic Disease; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007700:Kinetics; D008104:Liver Cirrhosis, Alcoholic / Q000188:drug therapy; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use; D008657:Metabolic Clearance Rate; D008875:Middle Aged
D008314:Malonates; C024808:diisopropyl 1,3-dithiol-2-ylidenemalonate