Abstract
Docetaxel, an efficient chemotherapeutic drug, exhibits low and variable oral bioavailability due to the active efflux by P-glycoprotein (P-gp) and more so to CYP3A4 gut metabolism. Using a spray-drying technique, docetaxel was incorporated in PLGA [poly(lactic-co-glycolic acid)] nanocapsules (NC) which were embedded in entero-coated microparticles. An oral administration of the NC formulation elicited a higher absolute bioavailability than both a docetaxel solution (276%) and a free docetaxel NC formulation (400%) injected intravenously, a 5-mg/kg dose. The batches (B) I and II NC formulations elicited C(max) values that were 1,735% and 2,254%, respectively; higher than the C(max) value of the oral docetaxel solution combined with blank microparticles, a 10-mg/kg dose. No significant difference in AUC (area under curve) was observed between the batches. These unexpected results can be explained only if the pharmacokinetics of docetaxel had been modified. It was shown that NCs released from the microparticles penetrated the enterocytes, bypassing P-gp; apparently circumventing gut metabolism and accumulating within the lymphatic system from where both intact or biodegraded NCs and free docetaxel were progressively released into the circulation as plausibly supported by the fluorescent imaging results. Furthermore, the circulating docetaxel in plasma was unencapsulated and circulated either in free form or bound to albumin. Both free docetaxel NCs and microparticles exhibited in vitro efficacy on WRC 256 cells suggesting that the activity of docetaxel was not altered. This delivery concept has potential for clinical translation, perhaps allowing docetaxel chemotherapy to be switched from intravenous to oral delivery.
Highlights
Docetaxel is an anticancer drug widely prescribed for the treatment of various cancers
P-gp/ CYP3A4 inhibitors succeeded in improving docetaxel oral bioavailability [8, 9]; but, their clinical applicability is problematic because their administration often induces adverse effects [10]
We present a novel oral formulation containing docetaxel–PLGA [poly(lactic-co-glycolic acid)] nanocapsules (NC) embedded in entero-coated bioadhesive microparticles, which significantly improve oral bioavailability of docetaxel without affecting the physiologic activity of the P-gp and CYP3A4
Summary
Docetaxel is an anticancer drug widely prescribed for the treatment of various cancers. Efforts are being dedicated to find alternative polysorbate-free formulations for oral administration [4] offering patient convenience, eliminating the risk of infection (intravenous catheters), and reducing hospital admissions. Docetaxel exhibits low and variable oral bioavailability due to active P-glycoprotein (P-gp) efflux and CYP3A4 metabolism in the gut wall [6, 7]. P-gp/ CYP3A4 inhibitors succeeded in improving docetaxel oral bioavailability [8, 9]; but, their clinical applicability is problematic because their administration often induces adverse effects [10]. We present a novel oral formulation containing docetaxel–PLGA [poly(lactic-co-glycolic acid)] nanocapsules (NC) embedded in entero-coated bioadhesive microparticles, which significantly improve oral bioavailability of docetaxel without affecting the physiologic activity of the P-gp and CYP3A4
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