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It is important to determine the relative contribution of each metabolic pathway (fp) and of enzymes to the net metabolism of a drug. The aim of this study was to investigate, using a human liver bank, the fp of the anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and the effects of various inhibitors and inducers on fp. The mean apparent Km and Vmax values (N=14) were 21±5 μM and 0.04±0.02 nmol/min/mg, respectively, for 6-methylhydroxylation, and 143±79 μM and 0.71±0.52 nmol/min/mg, respectively, for acyl glucuronidation in human liver microsomes. 6-Methylhydroxylation and acyl glucuronidation contributed 26 and 74%, respectively, to DMXAA metabolism at 5 μM; values were 7 and 93% at 350 μM DMXAA. There was a significant relationship between the ratio of metabolic activity by Phase II and I reactions (RII/I) and uridine diphosphate glucuronosyltransferase (UGT2B7) protein level (r=0.605, P=0.022), whereas a reverse correlation between RII/I and cytochrome P450 (CYP1A) protein level was observed (r=-0.540, P=0.046). Various compounds inhibited either DMXAA glucuronidation or 6-methylhydroxylation, or both pathways. Pretreatment of rats with β-naphthoflavone, but not phenobarbitone and cimetidine, increased the percentage of the contribution by 6-methylhydroxylation to 17% from 4% of control at 5 μM DMXAA. Our results indicate that the fp of DMXAA is subject to substrate concentration, inhibition, induction, and the protein levels of enzymes that biotransform DMXAA. However, clinical studies are important to verify the conclusions drawn from in vitro data.