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.
Guns
Emma S
ES
Dept. of Advanced Therapeutics, BC Cancer Agency, Vancouver, Canada.
Denyssevych
Tetyana
T
Dixon
Ross
R
Bally
Marcel B
MB
Mayer
Lawrence
L
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics; D004347:Drug Interactions / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000502:physiology*; D004358:Drug Therapy; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D017239:Paclitaxel / Q000493:pharmacokinetics*
D007093:Imidazoles; C410029:OC 144-093; D017239:Paclitaxel