Abstract
Abstract Purpose: To determine the mass balance, excretion and metabolism of the small molecule flavonoid tumor vascular disrupting agent ASA404 in patients with advanced cancer. Methods: Seven cancer patients were given a single dose of 3000 mg [14C] ASA404 by intravenous infusion over 20 minutes prior to collection of samples of plasma, urine and faeces. Pharmacokinetic samples were analysed by HPLC, liquid scintillation counting, mass spectrometry, glusulase treatment and comparison to authentic standards. Descriptive pharmacokinetic parameters were generated by non-compartmental analysis. Results: Mass balance was achieved (mean recovery of radioactivity in excreta = 86.9% of the dose) with balanced excretion between urine (mean recovery of radioactivity in urine = 53.9% of dose) and faeces (mean recovery of radioactivity in faeces = 33.3% of dose). ASA404 was eliminated as parent drug, three known metabolites (6-hydroxy-ASA404, ASA404 acyl glucuronide and 6-hydroxy-ASA404 acyl glucuronide) and as two novel metabolites (an ASA404 dimer and an ASA404 dimer glucuronide conjugate). Unchanged ASA404 was the major radioactivity component detected in plasma within the first 24 hours after dosing. At later time-points, irreversibly protein bound ASA404 and all of the metabolites that had been detected in excreta, contributed to total plasma radioactivity. Conclusion: This study defined the substantial excretion of ASA404, mainly as metabolites, in both urine (over half of the dose) and faeces (about one third of the dose) after intravenous administration. Two novel metabolites were identified that were not reported by previous studies using nonradioactive techniques. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 751. doi:1538-7445.AM2012-751
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