Summary
Pharmacological studies on Oltipraz [4-methyl-5(pyrazinyl-2)-1-2-dithiole-3-thione)] were conducted with normal healthy subjects using various doses and schedules. Administration of single doses (1, 2 and 3 mg/kg) resulted in detectable drug levels in the serum (mean peak serum concentrations 16, 61 and 205 ng, respectively) and urine. The t1/2 was short (4.4, 4.1 and 5.3 hours respectively) and no steady state was achieved after multiple daily doses for 12 days. Introduction of a loading dose during the first day produced a steady state when 1.5 and 2.0 mg/kg/day were used. Daily administration of Oltipraz sustained the steady state with insignificant variations. Consumption of a high fat diet increased the serum and urine concentrations of Oltipraz (30–60%) compared to the low fat diet. Two subjects experienced flatulence during the administration of the drug. One subject developed numbness and pain in the thumbs with occurrence of small purplishblack spots resembling those observed in subacute endocarditis. These changes disappeared 10 days after discontinuation of the drug. No changes in peripheral blood counts, biochemical profile or thyroid function tests were observed after four weeks of Oltipraz. Further studies with a larger number of healthy subjects are needed for clarification of the safety and biological efficacy of small doses of Oltipraz during chronic administration.
Similar content being viewed by others
References
Barreau M, Cortel C, Jeanmart C: 1,2-Dithiolethiones. Chem Abstr (15217R) 87:593, 1977
Leroy JP, Barreau M, Cortel C, Jeanmart C, Messer M, Benazet F: Laboratory studies of 35972 R.P., a new schistosomicidal compound. In: Current Chemotherapy Proceedings of the 10th International Congress of Chemotherapy Vol. 1. American Society of Microbiology, 1978, pp. 148–150.
Gentilini M, DuFlo B, Richard-Le-Noble D, Brucken G, Danis M, Niel G, Meunier Y: Assessment of 35972RP (Øltipraz) a new antischistosomal drug against s. haematobium, s. mansoni and s. intercalatum. Acta Trop 37:271–274, 1980
Bella H, Rahim A, Mustafa GA, Ahmed MAM, Wasfi S, Bennett JL: Oltipraz-antischistosomal efficacy in Sudanese infected with s. mansoni. Am J Trop Med Hyg 31:775–778, 1982
Bueding E, Dolan P, Leroy JP: The antischistosomal activity of oltipraz. Res Commun Chem Pathol Pharmacol 37:297–303, 1982
Ali HM, Homeida MMA, Sulaiman SM, Bennett JL: Diet controlled blood levels of oltipraz in healthy male subjects. J Antimicr Chemother 13:465–470, 1984
Pieron R, Lesobre Y, Mafart D, Lancastre F, Renard A, Simon J, Gregoire J, Basset P: Oltipraz in one day treatment of s. haematobium bilharziasis (pharmacokinetic data, therapeutic effects). Revue Med Int 2:231–237, 1981
Ali HM, Bennett JL, Sulaiman SM, Gailcot J: Method for determination of oltipraz, a new antischistosomal agent in blood. J Chromatography 305:465–469, 1984
Bennett JL, McMillan J, Dimitrov NV: High performance liquid Chromatographic method for the analysis of oltipraz in human serum and urine. J Chromatography 573:146–149, 1992
Bieder A, Decouvelaere B, Gaillard C, Depaire H, Heusse D, Ledoux D, Lemar M, LeRoy JP, Raynaud L, Snozzi C, Gregoire J: Comparison of the metabolism of oltipraz in the mouse, rat and monkey and in man. Arzneim Forsch 33:1289–1297, 1983
Heusse D, Marlard M, Bredenbac J, Decouvelaere B, LeRoy JP, Bieder A, Jumeau H: Disposition of14C-oltipraz in animals. Arzheim Forsch 35:1431–1436, 1985
Ansher SS, Dolan P, Bueding E: Chemoprotective effects of two dithiolthiones and of butylhydroxyanisole against carbontetrachloride and acetaminophen toxicity. Hepatology 3:932–935, 1983
Wattenberg LW, Bueding E: Inhibitory effects of 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3 thione (oltipraz) on carcinogenesis induced by benzo (a)-pyrene, diethylnitrosoamine and uracil mustard. Carcinogenesis 7:1379–1381, 1986
Rao CV, Nayini J, Reddy BS: Effect of oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole] on azoxymethaneinduced biochemical changes related to early colon carcinogenesis in male F344 rats. Proc Exp Biol Med 197:77–84, 1991
Davidson NE, Egner PA, Kensler TW: Transcriptional control of glutathione s-transferase gene expression by the chemoprotective agent 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz) in rat liver. Cancer Res 50:2251–2255, 1990
Boone CW, Kelloff GJ, Malone WE: Identification of candidate cancer chemopreventive agents and their evaluation in animal models and clinical trials: a review. Cancer Res 50:2–9, 1990
Moreau N, Martens T, Fleury MB, LeRoy JP: Metabolism of oltipraz and glutathione reductase inhibition. Biochem Pharmacol 40:1299–1305, 1990
Davies MH, Schamber GJ, Schnell RC: Role of glutathione in oltipraz-induced protection in acetaminophen or allyl alcohol hepatotoxicity in the male hamster. Toxicologist 7:100, 1987
Liu YL, Roebuch BD, Yager JD, Goodman JD, Kensler TW: Protection by 5-(2-pyrazinyI)-4-methyl-1-2-dithiole-3-thione (oltipraz). Against the hepatotoxicity of aflatoxin B, in the rat. Toxicol Appl Pharmacol 93:442–451, 1988
Wahba ZZ, Lawson TW, Stohohs SJ: Factors influencing the induction of DNA single strand breaks in rats 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicology 58:57–69, 1989
Teicher BA, Stemweden J, Herman TS, Ghoshal PK, Rosowsky A: 1,2-dithiole-3-thione and dithioester analogs: potential radioprotectors. Br J Cancer 62:17–22, 1990
Moon RC, Rao KVN, Detrisac CJ, Kelloff GJ: Retinoids chemoprevention of lung cancer. In: Wattenberg LW, Lipkin M, Boon C, Kelloff GJ (eds) Cancer Chemoprevention. CRS Press, Boca Raton, FL, 1992 (In Press)
Detrisac CJ, Thomas CF, Ratko TA, Kelloff GJ, Moon RC: Chemopreventive efficacy of chemically diverse compounds in mouse urinary bladder carcinogenesis. Proc. AACR 29:129, 1988
PCNONLIN-Statistical Analysis of General Nonlinear and Pharmacokinetic Models. Statistical Consultants Inc, Lexington, KY, 1989.
Pelletier LL, Petersdorf RG: Infective endocarditis. In: Principles of Internal Medicine. McGraw Hill Co, New York, NY, 1980, pp. 1112–1116.
Ellgail AB, Eitayeb M, Kardaman MW, Daffalla AA, Dixon HG, Fenwick A: Dose finding trial using oltipraz to treat school children infected with schistosoma mansoni in Gezira, Sudan. J Trop Med Hyg 88:101–104, 1985
Kardaman NW, Fenwick A, Igail ABE, Tayeb ME, Bennett JL, Daffalla AA: Field trials with oltipraz against schistosoma mansoni in the irrigated area. Sudan J Trop Med Hyg 88:95–100, 1985
Etude des Effets del'Oltipraz A Dose Unique sur la Vaso Motoricite des Extremites (Brochure provided by Rhône-Poulenc Company, Paris, France)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dimitrov, N.V., Bennett, J.L., McMillan, J. et al. Clinical pharmacology studies of Oltipraz — A potential chemopreventive agent. Invest New Drugs 10, 289–298 (1992). https://doi.org/10.1007/BF00944183
Issue Date:
DOI: https://doi.org/10.1007/BF00944183