Summary
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 µg/ml) than in controls (median 0.019 µg/ml). The median apparent oral clearance was approximately 50 times lower in cirrhotics (median 2.2l/min) than in healthy volunteers (118l/min). The apparent oral clearance was significantly correlated with indicators of portalsystemic 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.
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References
Audétat V, Preisig R, Bircher J (1977) Der Aminopyrin-Atemtest unter akuter Alkoholeinwirkung. Schweiz Med Wochenschr 107: 231–235
Bailar JC, Louis TA, Lavori PW, Polansky M (1984) Studies without internal controls. N Engl J Med 311: 156–162
Bircher J (1983) Quantitative assessment of deranged hepatic function: A missed opportunity? Semin Liver Dis 3: 275–284
Bircher J, Küpfer A, Gikalov J, Preisig R (1976) Aminopyrine demethylation measured by breath analysis in cirrhosis. Clin Pharmacol Ther 20: 484–492
Blaschke TF, Rubin PC (1979) Hepatic first-pass metabolism in liver disease. Clin Pharmacokinet 4: 423–432
Boyes RN, Scott DB, Jebson PJ, Godman MJ, Julian DG (1971) Pharmacokinetics of lidocaine in man. Clin Pharmacol Ther 12: 105–116
Feely J, Wilkinson GR, Wood AJ (1981) Reduction of liver blood flow and propranolol metabolism by cimetidine. N Engl J Med 304: 692–695
Finch CA, Huebers H (1982) Perspectives in iron metabolism. N Engl J Med 306: 1520–1528
Frei A, Zimmermann A, Weigand K (1984) The N-terminal propeptide of collagen type III in serum reflects activity and degree of fibrosis in patients with chronic liver disease. Hepatology 4: 830–834
Fujisawa K, Kimura K, Yamauchi M, Kitahara T, Kawase H, Watanabe Y, Ogura K, Nakajima H, Kameda H (1983) Studies on the lipotropic effect of malotilate on the development of fatty liver induced by orotic acid. In: Oda T, Tygstrup N (eds) Hepatotrophic agent malotilate. Proceedings of a Symposium on Malotilate 1982. Excerpta Medica, Amsterdam. Current Clinical Practise Series No. 10, pp 29–43
Gibaldi M, Perrier D (1981) Pharmacokinetics, 2nd edn. Marcel Dekker, New York Basel, p 449
Grandjean EM, Paumgartner G, Preisig R (1979) Die Gallensäurenkonzentration im Serum nach einer Testmahlzeit bei hepatobiliären Erkrankungen. Ein Vergleich mit quantitativen Tests der Leberfunktion. Schweiz Med Wochenschr 109: 1280–1284
Hahn EG (1984) Blood analysis of liver fibrosis. J Hepatol 1: 67–73
Huet PM, Villeneuve JP (1983) Determinance of drug disposition in patients with cirrhosis. Hepatology 3: 913–918
Igarashi S, Hatahara T, Funaki N (1983) Effects of malotilate on protein synthesis in partially hepatectomized normal and cirrhotic rat livers. In: Oda T, Tygstrup N (eds) Hepatotrophic agent malotilate, Proceedings of a Symposium on Malotilate 1982. Excerpta Medica, Amsterdam. Current Clinical Practise Series No. 10, pp 9–20
Imaizumi Y, Sugimoto T, Kasai T (1981) Effect of diisopropyl 1,3-dithiol-2-ylidenemalonate (NKK-105) of fatty liver induced by carbon tetrachloride. Jpn J Pharmacol 31: 15–21
Jacobs A, Worwood M (1975) Ferritin in serum, clinical and biochemical implications. N Engl J Med 292: 951–956
Katoh M, Kitada M, Satoh T, Kitagawa H, Sugimoto T, Kasai T (1981) Further studies on the in vivo effect of diisopropyl 1,3-dithiol-2-ylidenemalonate (NKK-105) on the liver microsomal drug oxidation system in rats. Biochem Pharmacol 30: 2759–2765
Katoh M, Kitada M, Satoh T, Kitagawa H, Sugimoto T, Kasai T (1980) Effect of diisopropyl 1,3-dithiol-2-ylidenemalonate on microsomal electron transport system in rat liver. J Pharm Dyn 3: 261–263
Keiding S, Johansen S, Morgensen CE, Solling K (1977) Kinetics of ethanol inhibition of galactose elimination in perfused pig liver. Scand J Clin Lab Invest 34: 487–494
Kitagawa H (1983) Effects of malotilate on cholesterol metabolism and microsomal electron transport in rat livers. In: Oda T, Tygstrup N (eds) Hepatotrophic agent malotilate. Proceedings of a Symposium on Malotilate 1982. Excerpta Medica, Amsterdam. Current Clinical Practise Series No. 10, pp 21–28
Monna T (1983) Effect of malotilate on experimental liver fibrosis (cirrhosis) induced by carbon tetrachloride or egg yolk sensitization. In: Oda T, Tygstrup N (eds) Hepatotrophic agent malotilate. Proceedings of a Symposium on Malotilate 1982. Excerpta Medica, Amsterdam. Current Clinical Practise Series No. 10, pp 44–53
Müller M, Isenschmid M, Bührer M, Bircher J (1984) Automated digital plethysmography in human pharmacology, a methodological study. Arzneimittelforsch/Drug Res 34: 702–706
Park BK (1982) Assessment of the drug metabolism capacity of the liver. Br J Clin Pharmacol 14: 631–651
Patwardan RV, Johnson RF, Hoyumpa A, Sheehan JJ, Desmond PV, Wilkinson GR, Branch RA, Schenker S (1981) Normal metabolism of morphine in cirrhosis. Gastroenterology 81: 1006–1011
Paumgartner G (1975) The handling of indocyanine green by the liver. Schweiz Med Wochenschr 105 [Suppl]: 1–30
Paumgartner G, Vasella DL, Herz E, Reichen J, Preisig R (1979) Hepatische Extraktion von Taurocholat und Indocyaningrün bei Patienten mit Lebererkrankungen. Z Gastroenterol 17: 753–761
Pauwels S, Geubel AP, Dive C, Beckers C (1982) Breath14CO2 after intravenous administration of (14C) aminopyrine in liver diseases. Dig Dis Sci 27: 49–56
Pentikainen PJ, Neuvonen PJ, Tarpila S, Syvalahti E (1978) Effect of cirrhosis of the liver on the pharmacokinetics of chlormethiazole. Br Med J 2: 861–863
Porchet H, Bircher J (1982) Noninvasive assessment of portal-systemic shunting: evaluation of a method to investigate systemic availability of oral glyceryl trinitrate by digital plethysmography. Gastroenterology 82: 629–637
Rojkind M, Kershenobich D (1983) Liver fibrosis, a dynamic process? In: Csomos G, Thaler H (eds) Clinical hepatology. Springer, Berlin Heidelberg New York
Sachs L (1978) Angewandte Statistik, 5th edn. Springer, Berlin Heidelberg New York
Shull HJ, Wilkinson GR, Johnson R (1976) Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Ann Intern Med 84: 420–425
Sugimoto T (1983) Malotilate, an overview. In: Oda T, Tygstrup N (eds) Hepatotrophic agent malotilate. Proceedings of a Symposium on Malotilate 1982. Excerpta Medica, Amsterdam. Current Clinical Practise Series No. 10, pp 1–8
Suzuki H, Ichida F, Takino T, Nagashima H, Hirayama C, Fujisawa K, Furuta S, Monna T, Yamamoto S, Oda T (1983) Therapeutic effects of malotilate on chronic hepatitis and liver cirrhosis: A double-blind, controlled multicenter trial. In: Oda T, Tygstrup N (eds) Hepatotrophic agent malotilate. Proceedings of a Symposium on Malotilate 1982. Excerpta Medica, Amsterdam. Current Clinical Practise Series No. 10, pp 54–68
Tygstrup N (1966) Determination of the hepatic elimination capacity (Lm) of galactose by single injection. Scand J Clin Lab Invest 18 [Suppl 92]: 118–125
Weigand K, Zaugg PY, Frei A, Zimmermann A (1984) Long term follow-up of the N-terminal propeptide of collagen type III in serum of patients with chronic liver disease. Hepatology 4: 835–838
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Bührer, M., Le Cotonnec, J.Y., Wermeille, M. et al. Treatment of liver disease with malotilate. A pharmacokinetic and pharmacodynamic phase II study in cirrhosis. Eur J Clin Pharmacol 30, 407–416 (1986). https://doi.org/10.1007/BF00607952
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DOI: https://doi.org/10.1007/BF00607952