Interactions of patupilone (Epothilone B) with multidrug transporter proteins

Proc Amer Assoc Cancer Res, Volume 46, 2005 3430 Patupilone (Epothilone B, EPO906) is a potent non-taxane anti-microtubule agent currently undergoing Novartis-sponsored phase-II trials for diverse solid tumours including prostate, breast, colon, lung, renal and ovarian carcinomas. Epothilones and taxanes, despite being structurally unrelated, share their mechanism of action, thus binding beta-tubulin to inhibit microtubule depolymerisation with consequent malformation of mitotic spindles. Taxanes are subject to drug resistance and pharmacokinetic interactions detrimental to optimal dosing, mediated by the multidrug transporter proteins P-glycoprotein and, to a lesser extent, members of the large ABCC (MRP) subfamily. One of the most favourable characteristics of patupilone is that it is not a significant substrate of P-glycoprotein or the multidrug resistance associated protein Nevertheless, at least eight multidrug transporters are currently known and few of the potential interactions with epothilones have been studied previously. For example, apart from being substrates for transport, anticancer drugs may also alter the activity of the transporter proteins or their expression. We have systematically examined the interactions of patupilone with seven multidrug transporters in vitro: MDR1-type P-glycoprotein (ABCB1), the Breast Cancer resistance protein BCRP (ABCG2) and the Multidrug Resistance-associated Proteins 1 through 5 (ABCC1-5). Patupilone was not found to be a significant substrate of any of the transporters, or to alter their activity for test substrates. Patupilone is therefore unlikely to suffer from drug resistance, variations in bioavailability or drug-drug interactions mediated by the currently known multidrug transporters. We will also report on current studies of the effects of patupilone on drug transporter expression.