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Drug Metab Dispos ; 42(2): 207-12, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24212376

RESUMO

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.


Assuntos
Compostos de Anilina/farmacocinética , Antineoplásicos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Linfa/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacocinética , Administração Oral , Compostos de Anilina/administração & dosagem , Compostos de Anilina/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Área Sob a Curva , Disponibilidade Biológica , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/química , Cães , Jejum/metabolismo , Meia-Vida , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Modelos Animais , Período Pós-Prandial , Solubilidade , Sulfonamidas/administração & dosagem , Sulfonamidas/química , Ducto Torácico
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