Oltipraz: A laboratory and clinical review

Abstract Oltipraz [5‐(2‐pyrazinyl)‐4‐methyl‐1,2‐dithiole‐3‐thione; RP 35972] is a synthetic, substituted 1,2‐dithiole‐3‐thione previously used in humans as an antischistosomal agent. Cruciferous vegetables ( e.g. , Brussels sprouts, cabbage) contain several agents, including dithiolethiones, which appear to inhibit carcinogenesis; however, it is unclear which dietary compounds produce the protective effects. Animal studies have demonstrated that oltipraz is a potent inducer of Phase II detoxification enzymes, most notably glutathione‐ S ‐transferase (GST). Laboratory evaluations have shown that dietary concentrations of oltipraz produce marked inhibition of aflatoxin B 1 ‐induced hepatic tumorigenesis in rats. Levels of hepatic aflatoxin–DNA adducts, urinary aflatoxin–N 7 ‐guanine, and serum aflatoxin–albumin adducts decreased when biliary elimination of aflatoxin–glutathione conjugants increased, thus providing predictive biomarkers that measured a chemopreventive effect. In other animal experiments, oltipraz was found to inhibit chemically induced carcinogenesis in bladder, colon, breast, stomach, and skin cancer models. In addition, oltipraz has been shown to be non‐mutagenic, a radioprotector, and a chemoprotective agent against carbon tetrachloride and acetaminophen toxicity. More recent studies in rats suggest that unsubstituted 1,2‐dithiole‐3‐thiones may more effectively inhibit aflatoxin–induced hepatic tumorigenesis and induce electrophile detoxification enzymes. Multiple human clinical trials have been conducted using 1.0–4.5 gram doses of oltipraz over 1–3 days for the treatment of schistosomiasis. Phototoxicity has precluded its use in tropical areas. More recently, a 6 month Phase I trial was completed in which patients with resected colon polyps, or females with first degree relatives with breast cancer, were given oral daily doses of oltipraz at 125 mg or 250 mg. The maximum tolerated dose of oltipraz was ≥ 125 mg daily. Grade I/II toxicities included photosensitivity/heat intolerance, GI and neurologic toxicity. Peak plasma concentrations were analyzed by HPLC with wide variability. In another Phase I study, a single oral dose of oltipraz was given to normal volunteers at dose levels of 125, 250, 375, and 500 mg. There was no significant difference in half‐life (t ½ ) between the four dose levels nor in clearance at the 125 and 250 mg levels. Peak oltipraz levels ≥1.0 μg/mL were achievable with marked interpatient variability. A series of small trials evaluating single oral doses of oltipraz for up to 28 days (dosing range 1 mg/kg‐3 mg/kg/day) also showed a short t ½ (4.1–5.3 hours), a sustained steady state without variation after a loading dose, and increased serum and urine concentrations with consumption of a high‐fat diet. Future human clinical trials will include pharmacokinetic analyses of lower chronic dose administration of oltipraz with determination of intermediate endpoints in target tissues.