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.