CONCENTRATION-TIME COURSE OF NIRIDAZOLE AND 6 METABOLITES IN THE SERUM OF 4 FILIPINOS WITH SCHISTOSOMA-JAPONICUM INFECTION

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Abstract
Niridazole and 6 of its metabolites were quantitated by high-pressure liquid chromatography in sera of 4 male Filipino patients with mild Schistosoma japonicum infections given single oral doses of niridazole (15 mg/kg) on 2 occasions 10 days apart. Of the 5 oxidative metabolites measured, 4-hydroxyniridazole and 4-ketoniridazole achieved the highest concentrations, reaching peak values of 0.9 .+-. 0.3 .mu.g/ml of serum (mean .+-. S.D. n = 4) and 0.7 .+-. 0.1 .mu.g/ml of serum within 1-4 h. 4-Ketoniridazole achieved peak serum levels 1 h after the other oxidative metabolites in 3 of 4 patients and was the predominant metabolite in the serum of all patients 6-10 h after dosing. By 24 h, both 4-ketoniridazole and 4-hydroxyniridazole had largely disappeared from the serum. Niridazole and 3 other oxidative metabolites, 4,5-dihydoxyniridazole, 5-hydroxyniridazole and 4,5-dehydroniridazole, appeared wthin 1 h in serum but failed to exceed 0.4 .mu.g/ml; none of these compounds were detected in the 24 h serum samples. The pharmacokinetic pattern of niridazole and the oxidative metabolites showed marked interindividual variation, but was quite reproducible in the same individual studied 10 days later. 1-Thiocarbamoyl-2-imidazolidinone was analyzed in serum samples by a different high-pressure liquid chromatographic procedure. This reductive metabolites attained maximal levels of 50-150 ng/ml of serum 6-12 h after drug administration and remained at .gtoreq. 40% of its peak concentration even after 24 h. The persistence of 1-thiocarbamoyl-2-imidazolidinone in serum after a single oral dose of niridazole is consistent with its proposed role in mediating the prolonged immunosuppressive side effects of niridazole.