title: The role of lymphatic transport on the systemic bioavailability of the Bcl-2 protein family inhibitors navitoclax (ABT-263) and ABT-199.
abstract: Navitoclax (ABT-263), a Bcl-2 family inhibitor and ABT-199, a Bcl-2 selective inhibitor, are high molecular weight, high logP molecules that show low solubility in aqueous media. While these properties are associated with low oral bioavailability (F), both navitoclax and ABT-199 showed moderate F in preclinical species. The objective of the described study was to determine if lymphatic transport contributes to the systemic availability of navitoclax and ABT-199 in dogs. The intravenous pharmacokinetics of navitoclax and ABT-199 were determined in intact (noncannulated) dogs. In oral studies, tablets (100 mg) of navitoclax and ABT-199 were administered to both intact and thoracic lymph duct-cannulated (TDC) dogs. The clearance of navitoclax and ABT-199 was low; 0.673 and 0.779 ml/min per kilogram, respectively. The volume of distribution of both compounds was low (0.5-0.7 l/kg). The half-lives of navitoclax and ABT-199 were 22.2 and 12.9 hours, respectively. The F of navitoclax and ABT-199 were 56.5 and 38.8%, respectively, in fed intact dogs. In fed TDC dogs, 13.5 and 4.67% of the total navitoclax and ABT-199 doses were observed in lymph with the % F of navitoclax and ABT-199 of 21.7 and 20.2%, respectively. The lower lymphatic transport of ABT-199 corresponds to the lower overall % F of ABT-199 versus navitoclax despite similar systemic availability via the portal vein (similar % F in TDC animals). This is consistent with the higher long chain triglyceride solubility of navitoclax (9.2 mg/ml) versus ABT-199 (2.2 mg/ml). In fasted TDC animals, lymph transport of navitoclax and ABT-199 decreased by 1.8-fold and 10-fold, respectively.
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (E.F.C., J.B.) and Pharmaceutics (J.W.L.), Genentech Inc, South San Francisco, California; Department of Drug Metabolism and Pharmacokinetics, WuXi AppTec (Suzhou) Co., Ltd, Suzhou, Jiangsu Province ,China (C.Z.); Departments of Physical Chemistry (N.D.C.), Drug Metabolism (G.J., R.V.) and Cancer Research (A.J.S.), AbbVie, North Chicago, Illinois.
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
authors.forename: Chunqiang
authors.initials: C
authors.lastname: Zhu
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lubach
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Catron
authors.forename: Gary
authors.initials: G
authors.lastname: Jenkins
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.forename: Richard
authors.initials: R
authors.lastname: Voorman
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D005215:Fasting / Q000378:metabolism; D006207:Half-Life; D007275:Injections, Intravenous; D008196:Lymph / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D023421:Models, Animal; D019518:Postprandial Period; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D012995:Solubility; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013897:Thoracic Duct
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax; C528561:navitoclax