Mass balance, excretion and metabolism of [¹⁴C] ASA404 in cancer patients in a phase I trial.
OBJECTIVE
To determine the mass balance, excretion and metabolism of the small molecule flavonoid tumour vascular disrupting agent ASA404 in patients with advanced cancer.


METHODS
Seven cancer patients were given a single dose of 3,000 mg [(14)C] ASA404 by intravenous infusion over 20 min 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 noncompartmental 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-methylhydroxy-ASA404, ASA404 acyl glucuronide and 6-methylhydroxy-ASA404 acyl glucuronide) and 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 h 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.


CONCLUSIONS
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.
Cancer Clinical Pharmacology Research Group, Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, 85 Park Road, Grafton, Auckland 1142, New Zealand. m.mckeage@auckland.ac.nz
M J
MJ
McKeage
P C
PC
Fong
X
X
Hong
J
J
Flarakos
J
J
Mangold
Y
Y
Du
C
C
Tanaka
H
H
Schran
D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D013997:Time Factors; D044004:Xanthones
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D044004:Xanthones; C066668:vadimezan