Gender differences in the metabolism and pharmacokinetics of the experimental anticancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).

Abstract

Marked gender differences in the pharmacokinetics of many drugs have been reported. For the investigational anticancer drug, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), negligible gender differences in the plasma pharmacokinetics have been observed in mice. The gender effects on the plasma pharmacokinetics of DMXAA were further investigated using the rat model. In addition, the in vitro metabolism and plasma protein binding of DMXAA in male and female mice, rats and humans were investigated. DMXAA was administered to male and female rats by intravenous injection. DMXAA and its major metabolites formed in liver microsomes were determined by HPLC. Unbound DMXAA in plasma was separated by ultrafiltration followed by HPLC determination. In vivo kinetic studies indicated that female rats had 60%, 55% and 73% higher area under the plasma concentration-time curve (AUC) of DMXAA (2413 +/- 188 vs 1505 +/- 312 microM x h, P<0.05), elimination half-life (2.40 +/- 0.45 vs 1.55 +/- 0.33 h) and maximal plasma concentration (Cmax) (1236 +/- 569 vs 716 +/- 280 micro M), but 61% lower plasma clearance than male rats. In vitro studies indicated that male rats had a 67% higher glucuronidation activity (0.75 +/- 0.03 nmol/min per mg) than female rats (0.45 +/- 0.01 nmol/min per mg), resulting in a 96% faster intrinsic clearance (CL(int)) in the males than the females (6.36 +/- 0.65 vs 3.24 +/- .42 ml/min per g, P< 0.05). In contrast, female rats had 25% higher 6-methylhydroxylation activity (0.045 +/- 0.003 nmol/min per mg) than male rats (0.036 +/- 0.002 nmol/min per mg), resulting in a 57% faster intrinsic clearance (CL(int)) in the females than males (0.36 +/- 0.06 vs 0.23 +/- 0.05 ml/min per g). Overall, total CL(int) by both glucuronidation and 6-methylhydroxylation in male rats was 83% higher than in female rats (6.59 +/- 2.11 vs 3.60 +/- 1.07 nmol/min per g). Men ( n=4) had a significantly lower ( P<0.05) CL(int) for glucuronidation than women ( n=10), but a higher CL(int) for 6-methylhydroxylation, resulting in significantly higher total CL(int) in women than men (5.63 vs 8.33 nmol/min per g). There was no significant difference in either the total plasma protein or albumin concentration between male and female mice, rats or humans. There were significant gender-related differences in the metabolism and pharmacokinetics in the rat, in contrast to the mouse. This indicates a limited usefulness of the rat as a model for the study of DMXAA metabolism in relation to gender differences, although the gender differences in the in vitro metabolic capacity for DMXAA may provide an explanation for the gender differences in the pharmacokinetics in rats. Data from human liver microsomes may allow the prediction of gender effects in the in vivo pharmacokinetics of DMXAA.