Pharmacokinetics and bioreductive metabolism of the novel benzotriazine di-N-oxide hypoxic cell cytotoxin tirapazamine (WIN 59075; SR 4233; NSC 130181) in mice.
The novel benzotriazine di-N-oxide SR 4233 (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide) shows high selective cytotoxicity toward hypoxic tumor cells. We investigated its pharmacokinetics and bioreductive metabolism in mouse plasma, brain, liver and tumor in vivo and also tumor metabolism in vitro. Plasma elimination T1/2 increased slightly with dose, and metabolite kinetics were dose-dependent. Peak concentration and area under the curve0-infinity increased linearly with dose from 0.1 to 0.3 mmol kg-1 i.v. After 0.2 mmol kg-1 i.v., elimination was biphasic (T1/2 alpha < 2 min; T1/2 beta, 26.5 min). Peak plasma concentration and area under the curve0-infinity were 26 and 13.6 micrograms ml-1 hr, respectively. Peak plasma concentration for the two-electron reduction product SR 4317 (3-amino-1,2,4-benzotriazine-1-oxide) was 7 to 9 micrograms ml-1 and for the four-electron reduction product SR 4330 (3-amino-1,2,4-benzotriazine) peak plasma concentration was 0.5 to 1.0 micrograms ml-1. Identical results were obtained after i.p. administration. Oral dosing gave lower peak plasma drug concentrations (2-3 micrograms ml-1) but reasonable bioavailability (75%). SR 4233 underwent extensive bioreduction in KHT tumors. Tumor/plasma ratios (percentages) for SR 4233 were 32% compared to 174 (SR 4317) and 196% (SR 4330), respectively. Similar SR 4233 tissue/plasma percentages were obtained in RIF-1 and 16C tumors, but EMT6 tumors were markedly lower at 7%. Reduction also occurred with tumor homogenates in vitro (KHT = EMT6 > RIF-1). Conversion to SR 4317 and SR 4330 was more extensive in liver, with tissue/plasma percentages between 50 to 220 and 500 to 1800%, respectively. The brain showed a similar pattern to tumors. Urinary recoveries (0-8 hr) were low at 4.5% for SR 4233 and 0.4% for the reduced metabolites. A further 30% occurred as a glucuronide. Concentrations of SR 4233 required for effective in vitro cytotoxicity are achieved in vivo, and extensive bioreductive metabolism occurs in tumor and normal tissues.
MRC Clinical Oncology and Radiotherapeutics Unit, Medical Research Council Centre, Cambridge, United Kingdom.
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Walton
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Workman
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D015687:Cell Hypoxia; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D010084:Oxidation-Reduction; D000077704:Tirapazamine; D014227:Triazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine
D000970:Antineoplastic Agents; D001798:Blood Proteins; D014227:Triazines; D000077704:Tirapazamine