EFFECT OF CREMOPHOR-EL ON THE PHARMACOKINETICS, ANTITUMOR-ACTIVITY AND TOXICITY OF DOXORUBICIN IN MICE

Cremophor EL (CR) is a solubilizing agent and a modulator of P-glycopr otein (P-gp)-mediated anticancer multidrug resistance. The present stu dy was undertaken to evaluate whether doxorubicin (Dox) pharmacokineti cs, therapeutic activity and cardiotoxicity in Swiss albino mice is mo dified when combined with CR treatment. CR (2.5 ml/kg, i.p) given simu ltaneously with Dox (20 mg/kg, i.p,) increased Dox levels in plasma, h eart, liver and kidneys of healthy mice. Using an Ehrlich ascites carc inoma (EAC)-bearing mice experimental model, CR (2.5 ml/kg) improved t he survival and antitumor activity of Dox, The enhanced antitumor acti vity of Dox was related to a significant increase in EAC tumor cellula r Dox content by CR, Furthermore, CR (1 mu g/ml) potentiated the in vi tro cytotoxicity of Dox in cultured EAC cells. In healthy mice, Dox-in duced mortality was markedly reduced by simultaneous treatment with CR . CR enhanced DOX-induced increase in plasma lactate dehydrogenase, cr eatine phosphokinase (CPK) and CPK-MB isozyme activities, as well as t he cardiac malondialdehyde level. CR also increased Dox-induced focal necrotic myocardial lesions. These findings suggest that CR increased DOX antitumor activity and cardiotoxicity as a result of enhancing its bioavailability, and decreased cox-induced mortality in mice by a mec hanism not yet defined. [(C) 1998 Lippincott Williams & Wilkins.].