Summary
The MDR modulator, OC144-093, is a potential candidate for use in cancer therapy and exhibits potent biological activityin vitro andin vivo when combined with anticancer agents such as paclitaxel [1]. Its inhibitory interaction with P-glycoprotein (Pgp), the mdr1 gene product and a mechanistic participant in multidrug resistance [2], underlies its activity as a modulator of MDR. Having previously shown that OC144-093 is not a substrate for CYP3A [4] we first examined the effects of OC144-093 on paclitaxel metabolismin 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 μM, 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 OC144-993. 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 OC144-093. These results warrant the further clinical assessment of OC144-093 as an MDR reversing agent.
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Abbreviations
- PgP:
-
P-glycoprotein
- MDR:
-
multidrug resistance
- HPLC:
-
high performance liquid chromatography
- AUC:
-
area under the curve
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Guns, E.S., Denyssevych, T., Dixon, R. et al. Drug interaction studies between paclitaxel (Taxol) and OC144-093 — A new modulator of MDR in cancer chemotherapy. Eur. J. Drug Metab. Pharmacokinet. 27, 119–126 (2002). https://doi.org/10.1007/BF03190426
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DOI: https://doi.org/10.1007/BF03190426