Plasma disposition, metabolism and excretion of the experimental antitumour agent 5,6-dimethylxanthenone-4-acetic acid in the mouse, rat and rabbit
| Autor: | James W. Paxton, Philip Kestell, Gordon W. Rewcastle, Bruce C. Baguley, Ingrid C. Dunlop |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Cancer Research Time Factors Metabolic Clearance Rate Xanthones Glucuronidation Antineoplastic Agents Pharmacology Toxicology High-performance liquid chromatography Excretion Rats Sprague-Dawley Mice New Zealand white rabbit Pharmacokinetics Species Specificity Blood plasma Animals Pharmacology (medical) Infusions Intravenous Chromatography High Pressure Liquid Chromatography biology Dose-Response Relationship Drug Chemistry Blood Proteins biology.organism_classification Blood proteins Rats Oncology Xanthenes Injections Intravenous Rabbits Glucuronide Protein Binding |
| Zdroj: | Cancer chemotherapy and pharmacology. 43(4) |
| ISSN: | 0344-5704 |
| Popis: | 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an experimental antitumour agent currently undergoing phase I clinical trial, has a maximum tolerated dose (MTD) in male BDF1 mice of 99 micromol/kg. We have found the male Sprague-Dawley rat and the New Zealand White rabbit to have greater tolerance to DMXAA, with MTDs being 990 and 330 micromol/kg, respectively. To investigate the causes of this difference, we measured plasma and urine DMXAA concentrations by high-performance liquid chromatography (HPLC) after single i.v. bolus injections of 99 and 990 micromol/kg in the rat and following a bolus dose of 99 micromol/kg and a 10-min infusion of 330 micromol/kg in the rabbit. Following administration of DMXAA at the MTD in the mouse, rat and rabbit the maximal concentrations were 600, 2,200 and 1,708 microM, respectively, whereas areas under the concentration-time curves were 2,400, 19,000 and 2,400 microMh, respectively, for unchanged DMXAA. Data obtained for mice and rabbits were satisfactorily fitted to a two-compartment model with Michaelis-Menten kinetics. DMXAA was highly bound to plasma proteins, with the highest degree of binding being found in the rabbit. A small proportion of the total dose (7.8%, 0.6% and 12.4%, respectively) was excreted unchanged in urine over 24 h. This proportion increased (to 11.6%, 3.5% and 72.4%, respectively) following alkaline hydrolysis, suggesting the presence of glucuronide metabolites. Examination of rat and mouse urine by HPLC revealed the presence of two metabolites, which were characterized by mass spectrometry and nuclear magnetic resonance to be the acyl glucuronide of DMXAA and 6-(hydroxymethyl)-5-methylxanthenone-4-acetic acid. Thus, both mice and rats metabolise DMXAA by similar pathways. The results demonstrate considerable interspecies variations in tolerance to DMXAA that cannot be explained by differences in pharmacokinetics. |
| Databáze: | OpenAIRE |
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