Drug interaction studies between paclitaxel (Taxol) and OC144-093--a new modulator of MDR in cancer chemotherapy.

The MDR modulator, OC144-093, is a potential candidate for use in cancer therapy and exhibits potent biological activity in vitro and in vivo when combined with anticancer agents such as paclitaxel. Its inhibitory interaction with P-glycoprotein (Pgp), the mdr1 gene product and a mechanistic participant in multidrug resistance, underlies its activity as a modulator of MDR. Having previously shown that OC144-093 is not a substrate for CYP3A we first examined the effects of OC144-093 on paclitaxel metabolism in vitro. Using human liver microsomes, we have demonstrated that OC144-093 inhibited the CYP3A mediated metabolism of paclitaxel at high concentrations only (Ki = 39.8 +/- 5.1 microM, n=3). Pharmacokinetic results also show that an oral dose of OC144-093, co-administered with paclitaxel caused negligible disturbance of the pharmacokinetic profile for paclitaxel when injected intravenously. In contrast, AUC values were elevated approximately 1.5-fold in all groups treated orally with paclitaxel and OC144-093. Cmax was enhanced approximately 2-fold in the co-dosed group. These characteristics are consistent with Pgp blockade in the gut enhancing oral bioavailability. Elimination properties of paclitaxel were affected only upon multiple dosing of OC 144-093. These results warrant the further clinical assessment of OC144-093 as an MDR reversing agent.