A difference between the rat and mouse in the pharmacokinetic interaction of 5,6-dimethylxanthenone-4-acetic acid with thalidomide

Purpose: Coadministration of thalidomide, cyproheptadine or diclofenac has been shown to increase the area under the plasma concentration-time curve ( AUC) of the novel antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DM XAA) ill mice. The aim of this study was to further investigate these pharm acokinetic DMXAA-drug interactions in the rat model. Methods: The effects o f coadministration of L-thalidomide, cyproheptadine or diclofenac on the ph armacokinetics of DMXAA were investigated in male Wistar Kyoto rats. The ef fects of L-thalidomide, cyproheptadine and diclofenac on microsomal metabol ism and plasma protein binding of DMXAA were also investigated. Results. No significant alteration in the plasma concentration profile for DMXAA was o bserved following L-thalidomide pretreatment in rats. In contrast, when com bined with diclofenac or cyproheptadine, the plasma AUC of DMXAA was signif icantly (P < 0.05) increased by 48% and 88% and the T-1/2 by 36% and 107%, respectively, compared to controls. Both diclofenac and cyproheptadine at 5 00 muM caused a significant inhibition of DMXAA metabolism in rat liver mic rosomes. In contrast, L-thalidomide had no or little inhibitory effect on D MXAA metabolism in rat liver microsomes except for causing a 32% decrease i n 6-methylhydroxylation at 500 muM. None of the drugs had a significant eff ect on the plasma protein binding of DMXAA in the rat. Conclusion. These st udies showed that coadministration of L-thalidomide did not alter the plasm a DMXAA AUC in rats, in contrast to previous studies in mice, whereas diclo fenac and cyproheptadine significantly reduced the plasma clearance of DMXA A in rats in a similar manner to their effect in mice. The cause of the spe cies difference in the pharmacokinetic response to thalidomide by DMXAA is unknown, and indicates difficulties in predicting the outcome of such a com bination in patients.