In vitro and in silico methods to predict cytochrome P450 enzyme inhibition
Abstract
Cytochrome P450 (CYP) enzymes are important enzymes involved in drug metabolism.The CYP enzymes are a family of heme proteins involved in the metabolism of numerous toxic and pharmacologically active compounds and can cause drug-drug-interactions with co-administered drugs as well as unwanted adverse side effects.Several in vitro methods have been developed and are in widespread use to evaluate main kinetic properties (absorption, distribution, metabolism, excretion) in drug development projects.These studies help in identifying molecules that have favourable kinetic properties well before clinical studies in humans.The most modern technological breakthrough is the use of computational (in silico) methods to predict kinetic properties of lead molecules.In the present study, the overall goal was to develop novel in vitro and in silico methods to assess the metabolic features of xenobiotics.The metabolic focus of this thesis work is inhibition of CYP enzymes.The four aims of the present study were (1) to compare three in vitro inhibition screening tests for CYP enzymes (2) to create new inhibition structureactivity databases for human CYP enzymes (CYP1A2, CYP2B6, and CYP2E1) (3) to construct quantitative structure-activity relationship (QSAR) models of inhibitors of these enzymes and (4) to identify more potent and selective inhibitors for these enzymes.Three assay types, the traditional single substrate assays, the fluorescent probe method with recombinant human CYPs, and a…
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Evidence Hub reads this as a thesis, done in cell cultures (in vitro) and computer models (in silico), not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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