High Plasma Levels and Effective Lymphatic Uptake of Docetaxel in an Orally Available Nanotransporter Formulation

摘要: Docetaxel, an efficient chemotherapeutic drug, exhibits low and variable oral bioavailability due to the active efflux by P-glycoprotein (P-gp) more so CYP3A4 gut metabolism. Using a spray-drying technique, docetaxel was incorporated in PLGA [poly(lactic-co-glycolic acid)] nanocapsules (NC) which were embedded entero-coated microparticles. An administration of NC formulation elicited higher absolute than both solution (276%) free (400%) injected intravenously, 5-mg/kg dose. The batches (B) I II formulations Cmax values that 1,735% 2,254%, respectively; value combined with blank microparticles, 10-mg/kg No significant difference AUC (area under curve) observed between batches. These unexpected results can be explained only if pharmacokinetics had been modified. It shown NCs released from microparticles penetrated enterocytes, bypassing P-gp; apparently circumventing metabolism accumulating within lymphatic system where intact or biodegraded progressively into circulation as plausibly supported fluorescent imaging results. Furthermore, circulating plasma unencapsulated circulated either form bound albumin. Both exhibited vitro efficacy on WRC 256 cells suggesting activity not altered. This delivery concept has potential for clinical translation, perhaps allowing chemotherapy switched intravenous delivery. Cancer Res; 71(8); 3018–28. ©2011 AACR.