Review article

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

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

KAROLINA SŁOCZYŃSKA ; Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Krakow, Poland
AGNIESZKA GUNIA-KRZYŻAK ; Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy Jagiellonian University Medical College, 30-688 Krakow, Poland
PAULINA KOCZURKIEWICZ ; Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Krakow, Poland
KATARZYNA WÓJCIK-PSZCZOŁA ; Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Krakow, Poland
DOROTA ŻELASZCZYK ; Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy Jagiellonian University Medical College, 30-688 Krakow, Poland
JUSTYNA POPIÓŁ ; Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy Jagiellonian University Medical College, 30-688 Krakow, Poland
ELŻBIETA PĘKALA ; Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Krakow, Poland

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.

Keywords

metabolic stability; biotransformation; intrinsic clearance; in vitro half-life; metabolites; new chemical entity

Hrčak ID:

216135

URI

https://hrcak.srce.hr/216135

Publication date:

30.9.2019.

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