title: Pharmacokinetic studies of the herbicide and antitumor compound oryzalin in mice.
abstract: Oryzalin [3,5-dinitro-N,N-di(n-propyl)benzensulfanilamide] is a widely used sulfonamide herbicide that selectively inhibits microtubule formation in algae and higher plants. Oryzalin has also been found to be an inhibitor of intracellular free Ca2+ signaling in mammalian cells and to have antitumor activity in animals. Despite its widespread use there have been no reports of the pharmacokinetics of oryzalin in animals or man. A reversed-phase high-performance liquid chromatographic (HPLC) method was developed to measure oryzalin in biological fluids. Following repeated daily administration of oryzalin to mice by the i.p. route at 200 mg/kg, or the p.o. route at 300 mg/kg, peak plasma concentrations of up to 25 micrograms/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 identified 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-Depropyloryzalin caused similar inhibition of colony formation by HT-29 colon cancer cells as oryzalin with IC50 = 8 micrograms/ml. The results suggest that oryzalin and its N-depropyl metabolite can inhibit tumor colony formation at pharmacologically achievable levels.
authors.affiliation: Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson 85724-5024, USA.
authors.forename: K
authors.initials: K
authors.lastname: Dvorakova
authors.forename: R T
authors.initials: RT
authors.lastname: Dorr
authors.forename: A
authors.initials: A
authors.lastname: Gallegos
authors.forename: T
authors.initials: T
authors.lastname: McClure
authors.forename: G
authors.initials: G
authors.lastname: Powis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D004136:Dinitrobenzenes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006540:Herbicides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013424:Sulfanilamides; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004136:Dinitrobenzenes; D006540:Herbicides; D013424:Sulfanilamides; C012465:oryzalin