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Alternative Methods for Pulmonary-Administered Drugs Metabolism: a Breath of Change

Alternative Methods for Pulmonary-Administered Drugs Metabolism: a Breath of Change

Authors :
Lucio Mendes Cabral
Érika Yoko Suzuki
Alice Simon
Thaisa Francielle Souza Domingos
Bárbara de Azevedo Abrahim Vieira
Alessandra Mendonça Teles de Souza
Carlos Rangel Rodrigues
Valeria Pereira de Sousa
Flávia Almada do Carmo
Source :
Mini reviews in medicinal chemistry.
Publication Year :
2021

Abstract

Abstract: Prediction of pulmonary metabolites following inhalation of a locally acting pulmonary drug is essential to the successful development of novel inhaled medicines. The lungs present metabolic enzymes, therefore they influence drug disposal and toxicity. The present review provides an overview of alternative methods to evaluate the pulmonary metabolism for the safety and efficacy of pulmonary delivery systems. In vitro approaches for investigating pulmonary drug metabolism were described, including subcellular fractions, cell culture models and lung slices as the main available in vitro methods. In addition, in silico studies are promising alternatives that use specific software to predict pulmonary drug metabolism, determine whether a molecule will react with a metabolic enzyme, the site of metabolism (SoM) and the result of this interaction. They can be used in an integrated approach to delineate the major cytochrome P450 (CYP) isoforms to rationalize the use of in vivo methods. A case study about a combination of experimental and computational approaches was done using fluticasone propionate as an example. The results of three tested software, RSWebPredictor, SMARTCyp and XenoSite, demonstrated greater probability of the fluticasone propionate being metabolized by CYPs 3A4 at the S1 atom of 5-S-fluoromethyl carbothioate group. As the in vitro studies were not able to directly detect pulmonary metabolites, those alternatives in silico methods may reduce animal testing efforts, following the principle of 3Rs (Replacement, Reduction and Refinement), and contribute to the evaluation of pharmacological efficacy and safety profiles of new drugs in development.

Details

ISSN :
18755607
Database :
OpenAIRE
Journal :
Mini reviews in medicinal chemistry
Accession number :
edsair.doi.dedup.....c763d90b0353f1edb4b1d30f9e3ae79f