Strain differences in the liver microsomal metabolism of the experimental anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid in mice

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• 作者：Zhou ; Shufeng ; Kestell ; Philip ; Paxton ; James W.
• 刊名：Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences
• 出版年：2002
• 出版时间：September 5, 2002
• 年：2002
• 卷：776
• 期：2
• 页码：231-236
• 全文大小：153 K

文摘

The experimental anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mainly metabolised by acyl glucuronidation and to a lesser degree by 6-methyl hydroxylation. Strain differences in the maximum tolerated dose (MTD) of DMXAA in mice have been observed. The aim of this study was to compare the kinetics of DMXAA acyl glucuronidation and 6-methylhydroxylation in five various mouse strains, and correlate the in vitro metabolism data with MTD observed. In all mouse strains studied, DMXAA acyl glucuronidation and 6-methylhydroxylation in the liver microsomes followed Michaelis–Menten kinetics. Significant strain variations in the kinetic parameters (K_m, V_max and K_m/V_max, i.e., CL_int) for DMXAA acyl glucuronidation and 6-methylhydroxylation in mouse liver microsomes were observed. A 2–6-fold variation was spanned across strains for K_m, V_max and CL_int, respectively, for DMXAA glucuronidation and 6-methylhydroxylation. The rank order for total CL_int by glucuronidation and 6-methylhydroxylation was BDF1 (1.70 ml/min per g)>wild type of mice lacking IFN-γ receptor (0.80 ml/min per g)>nude mice (0.70 ml/min per g)>Swiss CD mice (0.56 ml/min per g)>C57Bl/6 mice (0.46 ml/min per g), with a 4-fold variation between the mouse strain of the highest and lowest CL_int. There was no significant correlation between total CL_int and MTD (r²