Identification and reactivity of the major metabolite (beta-1-glucuronide) of the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in humans.
1. The novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is extensively metabolized by glucuronidation and 6-methylhydroxylation, resulting in DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA). 2. The major human urinary metabolite of DMXAA was isolated and purified by a solid-phase extraction (SPE) method. The isolated metabolite was hydrolysed to free DMXAA by strong base, and by beta-glucuronidase. Liquid chromatography-mass spectrometry (LC-MS) and spectral data indicated the presence of a molecular ion [M + 1]+ at m/z 459, which was consistent with the molecular weight of protonated DMXAA-G. 3. The glucuronide was unstable in buffer at physiological pH, plasma and blood with species variability in half-life. Hydrolysis and intramolecular migration were major degradation pathways. 4. In vitro and in vivo formation of DMXAA-protein adducts was observed. The formation of DMXAA-protein adducts in cancer patients receiving DMXAA was significantly correlated with plasma DMXAA-G concentration and maximum plasma DMXAA concentration. 5. At least five metabolites of DMXAA were observed in patient urine, with up to 60% of the total dose excreted as DMXAA-G, 5.5% as 6-OH-MXAA and 4.5% as the glucuronide of 6-OH-MXAA. 6. These data suggest that the major metabolite in patients' urine is DMXAA beta-1-glucuronide, which may undergo hydrolysis, molecular rearrangement and covalent binding to plasma protein. The reactive properties of DMXAA-G may have important implications for the pharmacokinetics, pharmacodynamics and toxicity of DMXAA.
Zhou
S F
SF
Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand.
Paxton
J W
JW
Tingle
M D
MD
Kestell
P
P
Jameson
M B
MB
Thompson
P I
PI
Baguley
B C
BC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000302:isolation & purification* / Q000652:urine*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D010653:Phenylbutazone / Q000494:pharmacology; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D013997:Time Factors; D014859:Warfarin / Q000494:pharmacology; D014966:Xanthenes / Q000493:pharmacokinetics* / Q000652:urine; D044004:Xanthones
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D000970:Antineoplastic Agents; D018757:GABA Modulators; D020719:Glucuronides; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; D014859:Warfarin; D005966:Glucuronidase; D010653:Phenylbutazone; D003975:Diazepam