A chiral drugs

The question that must be addressed is which molecular species should be quantified in a bioequivalency study of a product containing a chiral drug ... 

Jimidar, M.I., Vennekens, T., Van Ael, W., Redlich, D., De Smef M. Optimization and validation of an enantioselective method for a chiral drug with eight stereo-isomers in capillary electrophoresis. Electrophoresis 2004, 25, 2876-2884. 

Even more subtle effects arise for drug interactions of a non-chiral drug with a chiral one. Phenylbutazone is not chiral in itself but it can interact with a chiral drug, warfarin, to change the activity of the latter. Phenylbutazone inhibits the oxidative metabolism of the (S)-(-) form of warfarin, (which is five times more potent than the (/ )-(+) form) and thereby decreases its clearance. Conversely, phenylbutazone induces the enzymatic reduction of the (/ ) form thus increasing the clearance.93 Analysis of total warfarin may indicate little departure from normal pharmacokinetics, but the distribution of eutomer and distomer will have changed markedly. 

However, the first mention of a three-point contact (between a chiral drug and its receptor) is found in an article by Easson and Stedman published in 1933 16W, and a year later, Max Bergmann postulated a three-point contact (involving COjH, H2N and the dipeptide linkage) between peptidases and the dipeptides hydrolyzed by them.16c) Both these publications seem to have been overlooked subsequently I thank Professors V. Prelog and H. Hirschmann, respectively, for drawing my attention to them. 

The R and S enantiomers of a molecule will have identical physical and chemical properties under most circumstances since they have identical energy contents and differ only at the three-dimensional level of their nonsuperimposability. However, the possibility that the two enantiomers of a chiral drug may differ in their biological effects is a phenomenon that has been recognized by pharmacologists since the beginning of the twentieth century. Table 13.2 presents some examples of chiral... 

Enantioselective synthesis is particularly important in the pharmaceutical industry, because only one enantiomer of a chiral drug is likely to have the desired effect. For example, levodopa [(- )-dopa or Z-dopa] is used in patients with Parkinson s disease to counteract a deficiency of dopamine, one of the neurotransmitters in the brain. Dopamine... 

If a chiral drug could be sold as a single active enantiomer, it should be possible to use smaller doses with fewer side effects. Many chiral drugs continue to be sold as racemic mixtures, however, because it is more difficult and therefore more costly to obtain a single enantiomer. An enantiomer is not easily separated from a racemic mixture because the two enantiomers have the same physical properties. In Chapter 12 we will study a reaction that can form a single active enantiomer, an important development in making chiral drugs more readily available. 

As discussed in Section 2 of this chapter. Tramadol is a chiral drug substance that is currently used as a high potency analgesic agent. The preparation of Tramadol is shovm in Fig 18.16, which results in the formation of all four possible stereoisomers from the Grig-... 

In principle, nanotubes with the Cig inside extract any lipophilic molecule. This ability to sequester lipophilic molecules can be viewed as a generic type of extraction selectivity, which might be useful in some apphcations. However, nanotubes that have molecular-recognition capability and extract only one particular molecule from solution might also be useful. We have shown that antibody-functionalized nanotubes can provide the ultimate in extraction selectivity—the extraction of one enantiomer of a chiral drug molecule. 

Similar to many other cases of biologically active compounds, stereochemistry influences the pharmacological effect of a chiral drug. This can be explained by the fact that there is only one energeticaUy favorable (specific) interaction of an active molecule with its receptor, both being chiral structures. Qualitative and quantitative differences are caused by different receptor affinities as demonstrated in Fig, 1 (1). The metabolism (biotransformation) of drugs is mainly caused by enzymes, which are chiral macromolecules and discriminate between substrate molecules of different stereochemistry, This may result in metabolites of different activity and in different pharmacokinetics, resorption, and excretion. Therefore, racemic drugs should be looked on as a 1 1 mixture of two different compounds. 

Figure 8 illustrates another pharmacokinetic issue that needs to be considered when selecting a study design or interpreting nonstereo-spedfic data for a chiral drug. In Fig. 8, the mean R S ratios from 12... 

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