<abstract xmlns="http://www.w3.org/1999/xhtml"><p>Determination of metabolic profiles of new chemical entities is a key step in the process of drug discovery, since it influences pharmacokinetic characteristics of therapeutic compounds. One of the main challenges of medicinal chemistry is not only to design compounds demonstrating beneficial activity, but also molecules exhibiting favourable pharmacokinetic parameters. Chemical compounds can be divided into those which are metabolized relatively fast and those which undergo slow biotransformation. Rapid biotransformation reduces exposure to the maternal compound and may lead to the generation of active, non-active or toxic metabolites. In contrast, high metabolic stability may promote interactions between drugs and lead to parent compound toxicity. In the present paper, issues of compound metabolic stability will be discussed, with special emphasis on its significance, <italic>in vitro</italic> metabolic stability testing, dilemmas regarding <italic>in vitro-in vivo</italic> extrapolation of the results and some aspects relating to different preclinical species used in <italic>in vitro</italic> metabolic stability assessment of compounds.</p></abstract>

Determination of metabolic profiles of new chemical entities is a key step in the process of drug discovery, since it influences pharmacokinetic characteristics of therapeutic compounds. One of the main challenges of medicinal chemistry is not only to design compounds demonstrating beneficial activity, but also molecules exhibiting favourable pharmacokinetic parameters. Chemical compounds can be divided into those which are metabolized relatively fast and those which undergo slow biotransformation. Rapid biotransformation reduces exposure to the maternal compound and may lead to the generation of active, non-active or toxic metabolites. In contrast, high metabolic stability may promote interactions between drugs and lead to parent compound toxicity. In the present paper, issues of compound metabolic stability will be discussed, with special emphasis on its significance, in vitro metabolic stability testing, dilemmas regarding in vitro-in vivo extrapolation of the results and some aspects relating to different preclinical species used in in vitro metabolic stability assessment of compounds.

Metabolic stability and its role in the discovery of new chemical entities

Department of Pharmaceutical Biochemistry, Faculty of Pharmacy

Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy

Acta Pharmaceutica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

{"article-title":"Metabolic stability and its role in the discovery of new chemical entities"}

Determination of metabolic profiles of new chemical entities is a key step in the process of drug discovery, since it influences pharmacokinetic...

Metabolic stability and its role in the discovery of new chemical entities

Publié en ligne: 26 juin 2019

Pages: 345 - 361

Accepté: 29 déc. 2018

DOI: https://doi.org/10.2478/acph-2019-0024

Mots clés
metabolic stability, biotransformation, intrinsic clearance, half-life, metabolites, new chemical entity

© 2019 Karolina Słoczyńska et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Metabolic stability and its role in the discovery of new chemical entities

Publié en ligne: 26 juin 2019

Pages: 345 - 361

Accepté: 29 déc. 2018

DOI: https://doi.org/10.2478/acph-2019-0024

Mots clésmetabolic stability, biotransformation, intrinsic clearance, half-life, metabolites, new chemical entity

© 2019 Karolina Słoczyńska et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Mots clés
metabolic stability, biotransformation, intrinsic clearance, half-life, metabolites, new chemical entity