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 B1-induced hepatic
tumorigenesis in rats. Levels of hepatic
aflatoxin-
DNA adducts, urinary aflatoxin-N7-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 < or = 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 (t1/2) between the four dose levels nor in clearance at the 125 and 250 mg levels. Peak
oltipraz levels > or = 1.0 microgram/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 t1/2 (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.(ABSTRACT TRUNCATED AT 400 WORDS)