Metabolism optical isomerism

Optical isomerism plays a vital role in living cells. Nearly all carbohydrates and amino acids are optically active, but only one of the isomers is biologically usable. For example, r/-glucose is metabolized for energy, but /-glucose is excreted unused. Similarly, /-alanine is incorporated naturally into proteins, but r/-alanine is not. Many drugs are chiral molecules of which one optical isomer is biologically active and the other has either a different type of activity or none at all. 

Are there any stereochemical requirements of local anesthetic compounds when they bind to the sodium channel receptors A number of clinically used local anesthetics do contain a chiral center (i.e., bupivacaine, etidocaine, mepivacaine, and prilocaine) (Table 16.2), but in contrast to cholinergic drugs, the effect of optical isomerism on isolated nerve preparations revealed a lack of stereospecificity. In a few cases (e.g., prilocaine, bupivacaine, and etidocaine), however, small differences in the total pharmacological profile of optical isomers have been noted when administered in vivo (41,42,43). Whether these differences result from differences in uptake, distribution, and metabolism or from direct binding to the receptor has not been determined. 

Yamaguchi, T. Nakamura, Y. Stereoselective metabolism of 2-phenyl-propionic acid in rat. II. Studies on the organs responsible for the optical isomerization of 2-phenylpropionic acid in rat in vivo. Drug. Metab. Disp. 1987, 15, 535-539. 

The enzyme occurs in mammalian liver and kidney, from which sources Krebs (1935) has separated two types L-deaminase, which attaclcs the natural amino acids, and which can be inhibited by octyl alcohol and D-deaminase, which oxidised the optically isomeric D-amino acids, and is not inhibited by octyl alcohol. Since these D-acids are foreign to living organism and not found in food proteins, the significance of their deaminase is obscure, unless it be to protect the animal from evolutionary freaks of metabolism and malignant growths (p. 136). 

Samples of known amounts of drugs were dissolved in CDCI3 containing the various CSAs as well as a known amount of internal standard (o-dimethoxybenzene) and H NMR spectra recorded on a 400-MHz instrument. It was checked whether the CSAs produced well-resolved peaks for both compounds, whether the CSAs were stable and had no resonances close to the signals of interest in ketoprofen, and whether the signals of the enantiomers of ketoprofen were well separated at reasonably low concentrations of the CSAs. With the exception of the naphthylethylamine, all CSAs produced good separations of optical isomer resonances, and so can be used to determine the isomeric ratio upon dissolution and metabolism. 

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