Strain differences in the liver microsomal metabolism of the experimental anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid in mice.
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-gamma 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 (r(2)=0.88, P>0.05), but the rank order for CL(int) was consistent with that for MTD. These results suggested that there were significant strain differences in DMXAA metabolism in mouse liver microsomes and the strain-related differences in the metabolism of DMXAA did not provide an explanation for the strain differences in the MTD.
Zhou
Shufeng
S
Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. shufeng.zhou@auckland.ac.nz
Kestell
Philip
P
Paxton
James W
JW
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism*; D013045:Species Specificity; D014966:Xanthenes / Q000378:metabolism* / Q000493:pharmacokinetics; D044004:Xanthones
D000970:Antineoplastic Agents; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan