PHARMACOKINETIC STUDIES OF THE HERBICIDE AND ANTITUMOR COMPOUND ORYZALIN IN MICE

Oryzalin [3,5-dinitro-N,N-di(n-propyl)benzensulfanilamide] is a widely used sulfonamide herbicide that selectively inhibits microtubule form ation in algae and higher plants. Oryzalin has also been found to be a n inhibitor of intracellular free Ca2+ signaling in mammalian cells an d to have antitumor activity in animals. Despite its widespread use th ere have been no reports of the pharmacokinetics of oryzalin in animal s or man. A reversed-phase high-performance liquid chromatographic (HP LC) method was developed to measure oryzalin in biological fluids. Fol lowing repeated daily administration of oryzalin to mice by the i.p. r oute at 200 mg/kg, or the p.o, route at 300 mg/kg, peak plasma concent rations of up to 25 mu g/ml were achieved. The half life for oryzalin in plasma of mice given i.p. oryzalin was 14.3 h with a clearance of 0 .07 l/h. A major metabolite of oryzalin, N-depropyloryzalin, was ident ified in plasma and its structure confirmed by mass spectral analysis (M + H+ = 305). This metabolite was cleared more rapidly than oryzalin with a half life of 1.15 h and a clearance of 0.17 l/h. N-Depropylory zalin caused similar inhibition of colony formation by HT-29 colon can cer cells as oryzalin with IC50 = 8 mu g/ml. The results suggest that oryzalin and its N-depropyl metabolite can inhibit tumor colony format ion at pharmacologically achievable levels. (C) 1997 Elsevier Science B.V.