Significance and challenges of stereoselectivity assessing methods in drug metabolism

Abstract

Stereoselectivity in drug metabolism can not only influence the pharmacological activities, tolerability, safety, and bioavailability of drugs directly, but also cause different kinds of drug–drug interactions. Thus, assessing stereoselectivity in drug metabolism is of great significance for pharmaceutical research and development (R&D) and rational use in clinic. Although there are various methods available for assessing stereoselectivity in drug metabolism, many of them have shortcomings. The indirect method of chromatographic methods can only be applicable to specific samples with functional groups to be derivatized or form complex with a chiral selector, while the direct method achieved by chiral stationary phases (CSPs) is expensive. As a detector of chromatographic methods, mass spectrometry (MS) is highly sensitive and specific, whereas the matrix interference is still a challenge to overcome. In addition, the use of nuclear magnetic resonance (NMR) and immunoassay in chiral analysis are worth noting. This review presents several typical examples of drug stereoselective metabolism and provides a literature-based evaluation on current chiral analytical techniques to show the significance and challenges of stereoselectivity assessing methods in drug metabolism.

Analysis of stereoisomers of chiral drug by mass spectrometry

“…In this method, the chiral analyte will react with the ligand forming identical ternary diastereomeric complexes (like protonated ternary complex (A R or S ) (ref) 2 + H) + and metal ion centered ternary complex [M II (A R or S )(ref) 2 -H] + ), which cannot be differentiated by single-stage MS. The enantiomers own different affinity toward the ligand caused by static electricity, hydrogen bonds, π-π conjugation, and spatial interaction, thus leading to different binding energy.…”

Chiral detection of entecavir stereoisomeric impurities through coordination with R‐besivance and ZnII using mass spectrometry

“…To avoid adverse effects and optimize the therapeutic value of enantiomeric drugs, it is necessary to isolate homochiral drugs from other isomers. Enantiomerically pure drugs have gained much attention in recent years because of their lower frequency of adverse drug reactions and optimized therapeutic effects . Homochiral drug R&D has become a hotspot in the pharmaceutical industry.…”

Direct differentiation of stereoisomers of ezetimibe/ambrisentan/atorvastatin and their mechanism study by electrospray ionization quadrupole time‐of‐flight mass spectrometry

“…Chirality is essential in life processes, and most of the bioactive compounds of living organisms are chiral molecules . In the pharmaceutical field, the enantiomers of a chiral drug show striking differences in terms of biological activity, potency, and toxicity; enantiomeric pure products are therefore desirable ones in drug candidates . For this reason, the US Food and Drug Administration (FDA) guidelines recommended the study of enantioselective identity and stability for the contributions of individual enantiomers to pharmacological and toxicological activity…”

“…1 In the pharmaceutical field, the enantiomers of a chiral drug show striking differences in terms of biological activity, potency, and toxicity; enantiomeric pure products are therefore desirable ones in drug candidates. 2,3 For this reason, the US Food and Drug Administration (FDA) guidelines recommended the study of enantioselective identity and stability for the contributions of individual enantiomers to pharmacological and toxicological activity. 1 Various of methods has been used for the separation of enantiomers, such as high-performance liquid chromatography (HPLC), gas chromatography (GC), supercritical fluid chromatography (SFC), thinlayer chromatography (TLC), and capillary electrophoresis (CE).…”

“…[4][5][6][7] By creating a chiral environment, chiral analysis has been accomplished using mass spectrometric methods. Among several purely MS-based methods for chiral analysis, one of the widely used is collision-induced dissociation (CID) of metal-bound trimeric complex ions, [M II (A)(Ref) 2 -H] + consisting of metal ions (M II ), an analyte (A), and two chiral references (Ref), in a MS/MS experiment. [8][9][10][11] Cooks' kinetic method contributed significantly to this area.…”