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Thursday, January 18, 2018

Your Chiral Center

Plainsboro, NJ, December 1, 2006 - About 25% of common drugs are racemates, i.e., a 50:50 mixture of enantiomers1. A recent review suggests that the proportion of single-enantiomer drugs among approved new chemical entities (NCEs) worldwide has been consistently greater than that of racemates2. Single-enantiomer drug development attempts to emphasize positive aspects of the enantiomer over the racemate, such as improved pharmacology, or pharmacokinetic profile, and deemphasize the negative aspects, such as mild or toxic side effects. Successful examples of so called "chiral switching" are Nexium (esomeprazole) the S enantiomer of omeprazole (the active ingredient in Prilosec), and Lexapro (escitalopram), the S enantiomer of citalopram (Celexa).

The condition for the creation of a stereoisomer is the presence of at least one asymmetric or chiral center (usually carbon)1. Enantiomers or optical isomers are stereoisomers that have the same chemical and physical properties but are mirror images (opposite sign of rotation of plane polarized light). When more than one chiral center is present, the yield of stereoisomers is 2n, where "n" is the number of chiral centers. Half of the pairs are enantiomers, and the other half are diastereomers. Diastereomers have the same structural formula but will usually exhibit different physical, chemical and pharmacological properties. The differential effects of single-enantiomer drugs may be the result of chiral drug targets – enzymes, receptors, or ion channels with stereospecific activity such that the pharmacological or toxicological activity to this target resides in only one of the stereoisomers.

The FDA policy statement for the development of new stereoisomeric drugs indicates that quantitative assays should be developed early in drug development to assess the potential for interconversion and the absorption, distribution, metabolism and excretion (ADME) profile of the individual isomers3. In addition, the pharmacology, PK, and toxicology of the enantiomers compared to the racemate must be considered. In the drug development process for enantiomers much focus has been given to stereoselective metabolism. For example, the stereoselective metabolism of Itraconazole (ITZ) in-vitro and in-vivo was recently studied4. ITZ has three chiral centers and is administered clinically as a mixture of four stereoisomers. It was observed in-vivo that ITZ disposition was stereoselective with a 3-fold difference in Cmax between the (2R, 4S)-ITX and the (2S, 4R)-ITZ pairs of diastereomers. In addition, metabolites detected in plasma were of the (2R, 4S) stereochemistry. The authors suggest from in-vitro studies that stereoselective metabolism and elimination by CYP3A4 occurs in-vivo.

In terms of LC/MS bioanalytical methods for quantitation, enantiomers require specialized chiral methods and associated chiral columns. In contrast, diastereomers are usually separable by achiral columns.

At XenoBiotic Laboratories, Inc. (XBL) we have extensive expertise in developing chiral methods for quantifying enantiomers, and in the analysis of in-vitro, pre-clinical, and clinical ADME properties of racemate and single-enantiomer NCEs (See XBL's Posters and Presentations page for a list of recent posters and publications related to chiral drug development). XBL provides complete bioanalytical and metabolism profiling services for chiral drugs in development using the latest and most sensitive LC/MS/MS instrumentation and outstanding technical know how.

XBL strives to offer the latest advances in technology — advances that bring greater value to the core services it provides to the pharmaceutical, biotechnology, animal health, and agrochemical industries.

References

  1. Patocka, J., Dvorak, A. Biomedical Aspects of Chiral Molecules, J. Applied Biomedicine, 2: 95-100, 2004.

  2. Agranat, I., Caner, H., Caldwell, J. Putting Chirality to Work: The Strategy of Chiral Switches, Nature Rev. Drug Discovery, 1: 753-768, 2002.

  3. FDA's Policy Statement for the Development of New Stereoisomeric Drugs.
    www.fda.gov/Cder/guidance/stereo.htm

  4. Kunze K., Nelson, W. Kharasch, E., Thummel, E., Isoherranen, N. Stereochemical Aspects of Intraconazole Metabolism in Vitro and In Vivo, Drug Metab. Dispos. 34(4): 583-590, 2006.