Natural and synthetic xenobiotics bioavailability on in vitro models

Abstract

Bioavailability study of a drug candidate is extremely important, in which knowledge of metabolism and absorption are important factors to assess safety and efficacy of the target compound as well as the understanding of the pharmacokinetic properties. Metabolism is the major route of elimination of a xenobiotic from human body, which directly affects its bioavailability. The main function of the phase I metabolism is to promote increased polarity of a xenobiotic by adding functional groups, oxidation and/or hydrolysis reactions, that facilitates their removal by kidney. In this context, some in vitro models, such as liver microsomes, supersomes, cytosolic fractions and liver S9 fractions, have been used in order to reproduce the biotransformation reactions that occur in humans. Furthermore, the use of biomimetic systems employing organometallic catalysts, such as metalloporphyrins, has been widely used, since it is ethical and effective methodologies for preliminary metabolism studies of a compound. In general, in vitro models enable the isolation of the metabolites, at an acceptable cost, for identification and structural characterization of the possible metabolites formed. Absorption is also an important step that limit the pharmacological action of a compound. Since the oral route is the most convenient for the administration of drugs, its absorption from the gastrointestinal tract is necessary to exert the desired effect. For a rapid evaluation of the permeability, many in vitro methods have been developed with different levels of complexity and sophistication, such as artificial lipid systems (PAMPA), animal tissues (segments of the gastrointestinal tract of pigs, inverted intestine sacs from rats) and cell cultures (Caco-2, TC-7, MDCK, 2/4/A1). The human colon adenocarcinoma cell line, Caco-2, is the better established in vitro model for predicting xenobiotic absorption, widely used in both academic research and pharmaceutical industries. The choice of the most suitable in vitro system to perform metabolism or absorption studies depends on in vivo similarity, cost, availability, ethical considerations and purpose of application of the results. Obtaining valid data that can be realistic extrapolated is a key point for the progress of the thematic project research (N° FAPESP 2014/50265-3). (AU)