title: High plasma levels and effective lymphatic uptake of docetaxel in an orally available nanotransporter formulation.
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.
authors.affiliation: Faculty of Medicine, The Institute for Drug Research, The School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Taher
authors.initials: T
authors.lastname: Nassar
authors.forename: Suha
authors.initials: S
authors.lastname: Attili-Qadri
authors.forename: Oshrat
authors.initials: O
authors.lastname: Harush-Frenkel
authors.forename: Shimon
authors.initials: S
authors.lastname: Farber
authors.forename: Shimon
authors.initials: S
authors.lastname: Lecht
authors.forename: Philip
authors.initials: P
authors.lastname: Lazarovici
authors.forename: Simon
authors.initials: S
authors.lastname: Benita
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002279:Carcinoma 256, Walker / Q000188:drug therapy / Q000378:metabolism; D000077143:Docetaxel; D019344:Lactic Acid / Q000008:administration & dosage; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D011100:Polyglycolic Acid / Q000008:administration & dosage; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D013608:Tablets, Enteric-Coated / Q000008:administration & dosage / Q000737:chemistry; D043823:Taxoids / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D013608:Tablets, Enteric-Coated; D043823:Taxoids; D000077143:Docetaxel; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid