Species differences in the metabolism of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid in vitro : implications for prediction of metabolic interactions in vivo

Abstract

1. Mouse studies have indicated that the antitumour effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) are dramatically potentiated in combination with other drugs, and it has been proposed that optimization of the therapeutic potential of DMXAA would exploit combination therapy. The aim was to identify the most appropriate animal model for further investigations of the pharmacokinetics of possible DMXAA-drug combinations and their extrapolation to patients. 2. Qualitatively, the metabolic profile for DMXAA in liver microsomes was similar in mouse, rat, rabbit and humans, with glucuronidation and 6-methylhydroxylation the two major metabolic pathways. In all species, the intrinsic clearance by glucuronidation was at least 2-fold that due to hydroxylation. There was significant variability in the in vitro kinetic parameters (K_m, V_max), with the mouse being the least efficient DMXAA metabolizer compared with the other species. 3. Mouse, rat and rabbit renal microsomes exhibited DMXAA glucuronidation activity, but only the rabbit showed 6-methylhydroxylation. For the total in vitro CL_int (V_max/K_m) by glucuronidation and 6-methylhydroxylation, the ratio of kidney:liver was 0.67, 0.03 and 0.34 in the mouse, rat and rabbit respectively. However, taking into account the liver and kidney weight difference, it is apparent that the in vivo renal metabolism would not be a major contributor to the overall elimination of DMXAA. 4. The inhibitory profile for liver DMXAA glucuronidation was similar across species, but there was remarkable interspecies variability in the inhibition of liver DMXAA 6-methylhydroxylation. 5. Extrapolation of in vitro intrinsic clearance to in vivo gave a significant underestimation of plasma clearance for all species. However, there was a significant allometric relationship for plasma clearance and volume of distribution, but not for maximum tolerated dose across species. 6. The results indicate that animal models may have a limited role in the extrapolation to patients of drug interactions with agents such as DMXAA that have immunomodulating activity that may vary widely between species.