Absorption, Distribution, Metabolism and Excretion (ADME) of Sorafenib and its two analogues of 2-aminoquinolone, in rat animal model, in silico – in vivo interplay

Abstract

The aim of this project is to synthesize Sorafenib two derivatives of 2-amino-6-phenoxyquinolone: AH1 & P64, then conduct ADME studies in healthy rats and correlate results with in vitro and in silico results. The absolute bioavailability of sorafenib derivatives were found very low 2.2 & 12 % for AH1 & P64 after in vivo oral and IV studies of the derivatives. Also, the relative bioavailability of sorafenib derivatives were found very low 0.3 & 0.6 % for AH1 & P64 after in vivo studies of sorafenib and its derivatives. In vitro stability tests showed stable derivatives in all degradation tests over the time course of the experiments which suggests stable derivatives in vivo too. However, in vitro diffusion study showed that derivatives permeability values are more than 60 times lower than sorafenib permeability which explains the low bioavailability of the derivatives as compared with sorafenib. Sorafenib derivatives were shown to have more in vitro anti-cancer activity, yet low in vivo bioavailability due to low intestinal permeability.

Keywords

• ADME
• ADMIT Lab
• sorafenib
• Pharmacokinetics

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