The Inhibition of First-Pass Metabolism of Beyond Lipinski's Rule of Five Compound by Pharmaceutical ExcipientTools Hashad, Valentina (2024) The Inhibition of First-Pass Metabolism of Beyond Lipinski's Rule of Five Compound by Pharmaceutical Excipient. MPhil thesis, University of Nottingham.
AbstractFirst pass metabolism in the liver and gut wall metabolism by cytochrome P450 3A (CYP3A) enzymes plays a critical role in limiting the bioavailability of compounds in the beyond Lipinski’s rule of 5 space. This study aims to evaluate the potential inhibitory effects of 4 excipients: PEG 400, lysolecithin, Tween 20, vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) on CYP3A (predominately CYP3A4). Experiments were conducted in-vitro using human liver microsomes using lopinavir as a model compound. Results indicate that PEG 400, lysolecithin and Tween 20 were found to have no inhibitory effects on lopinavir metabolism by CYP3A4. TPGS shows an inhibitory effect at concentrations < 132 µM (200 µg/mL). This makes TPGS an attractive excipient for consideration in a formulation for oral delivery of compounds in the beyond Lipinski’s rule of five space. Further evidence is needed to understand how TPGS exerts its effect.
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