Acta Pharm. 69 (2019) 345-361
Review
Metabolic stability and
its role in the discovery of new chemical entities
KAROLINA SŁOCZYŃSKA, AGNIESZKA GUNIA-KRZYŻAK, PAULINA KOCZURKIEWICZ,
KATARZYNA WÓJCIK-PSZCZOŁA, DOROTA ŻELASZCZYK, JUSTYNA POPIÓŁ and ELŻBIETA
PĘKALA
karolina.sloczynska@uj.edu.pl
1 Department of Pharmaceutical Biochemistry, Faculty of Pharmacy,
Jagiellonian University Medical College, 30-688 Krakow, Poland
2 Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of
Pharmacy Jagiellonian University Medical College, 30-688 Krakow, Poland
Accepted December 29, 2018
Published online January 21, 2019
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