Metabolism enantiomers

If a drug is used as a racemic mixture, often only one of the enantiomers is responsible for the desired pharmacological effect. The other enantiomer may have a lesser effect, or no effect, or may even be responsible for undesired side effects. One example is perhexiline. a racemic drug that was used to treat abnormal heart rhythms. This drug was responsible for a number of deaths in the 1980s because one enantiomer was metabolized much more slowly than the other and accumulated at toxic levels. If perhexiline had been marketed only as the more rapidly metabolized enantiomer, it might have been a safer drug. 

The term chiral recognition refers to a process m which some chiral receptor or reagent interacts selectively with one of the enantiomers of a chiral molecule Very high levels of chiral recognition are common m biological processes (—) Nicotine for exam pie IS much more toxic than (+) nicotine and (+) adrenaline is more active than (—) adrenaline m constricting blood vessels (—) Thyroxine an ammo acid of the thyroid gland that speeds up metabolism is one of the most widely used of all prescription... 

There are interesting examples of enantiomers that not only are found separately but also have different chemical properties when reacting with some reagent which is itself an enantiomer. For example (+ )-glucose is metabolized by animals and can be fermented by yeasts, but (—)-glucose has neither of these properties. The enantiomer ( + )-carvone smells of caraway whereas (—)-carvone smells of spearmint. 

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

In contrast to laboratory reactions, enzyme-catalyzed reactions often give a single enantiomer of a chiral product, even when the substrate is achiral. One step in the citric acid cycle of food metabolism, for instance, is the aconitase-catalyzed addition of water to (Z)-aconitate (usually called ris-aconitate) to give isocitrate. 

Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S" in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

In some cases the unwanted enantiomer can perturb other biological processes and cause catastrophic side effects. The use of enantiomerically pure compounds thus permits more specific drug action and the reduction in the amount of drug administered. Even in the cases where the other enantiomer is inactive, the work involved in its metabolism before secretion can be avoided. 

The hydrolysis of seven alkyl arenesulfinylalkanoates by the bacterium Corynebacterium equi IFO 3730 studied by Ohta and coworkers34 are recent examples of kinetic resolutions which give sulfoxides of high enantiomeric purity and in reasonable yield. Compounds 16a, 16b and 16c were recovered in 30 to 43% yield and in 90 to 97% e.e. The S enantiomers underwent hydrolysis more rapidly than the R isomers. Sulfoxide 17 was isolated in 22% yield and 96% e.e., but sulfoxide 18 was completely metabolized. Esters other than methyl gave inferior results. The acids formed upon hydrolysis, although detected, were for the most part further metabolized by the bacterium. 

Biocatalytic access to both antipodal sulfoxides was exploited in total syntheses of bioactive compounds, which is outlined in some representative examples. Biooxidation of functionalized dialkyl sulfides was utilized in the direct synthesis of both enantiomers of sulforaphane and some analogs in low to good yields and stereoselectivities (Scheme 9.27) [206]. This natural product originates from broccoli and represents a potent inducer of detoxification enzymes in mammalian metabolism it might be related to anticarcinogenic properties of plants from the cruciform family. All four possible stereoisomers of methionine (R = Me) and ethionine sulfoxides... 

The mandelate pathway in Pseudomonas putida involves successive oxidation to benzoyl formate and benzoate, which is further metabolized via catechol and the 3-ketoadipate pathway (Figure 8.35a) (Hegeman 1966). Both enantiomers of mandelate were degraded through the activity of a mandelate racemase (Hegeman 1966), and the racemase (mdlA) is encoded in an operon that includes the next two enzymes in the pathway—5-mandel-ate dehydrogenase (mdlB) and benzoylformate decarboxylase (mdlC) (Tsou et al. 1990). 

The need to develop and use chiral chromatographic techniques to resolve racemates in pesticide residues will be driven by new hazard and risk assessments undertaken using data from differential metabolism studies. The molecular structures of many pesticides incorporate chiral centers and, in some cases, the activity differs between enantiomers. Consequently, in recent years manufacturers have introduced resolved enantiomers to provide pesticides of higher activity per unit mass applied. For example, the fungicide metalaxyl is a racemic mix of R- and 5-enantiomers, both having the same mode of action but differing considerably in effectiveness. The -enantiomer is the most effective and is marketed as a separate product metalaxyl-M. In future, it will not be satisfactory to rely on hazard/risk assessments based on data from metabolism studies of racemic mixes. The metabolism studies will need to be undertaken on one, or more, of the resolved enantiomers. 

Flutamide is an androgen receptor antagonist that achieves peak concentrations approximately 2 to 4 hours after an oral dose. Flutamide is metabolized extensively, with a terminal half-life of about 8 hours. Bicalutamide achieves peak concentrations approximately 6 hours after the dose, with a terminal half-life of 6 to 10 days. Bicalutamide undergoes stereospecihc metabolism, where the S-enantiomer is cleared more rapidly by the liver than the -enantiomer. Nilutamide achieves peak serum concentrations between 1 to 4 hours after an oral dose and has a terminal half-life of 38 to 60 hours. Nilutamide is metabolized extensively, with less than 2% excreted as unchanged drug by the kidney. Side effects common to these agents are hot flashes, gynecomastia, and decreased libido. Flutamide tends to be associated with more diarrhea and requires three-times-daily administration, whereas bicalutamide is dosed once daily. Nilutamide may cause interstitial pneumonia and is associated with the visual disturbance of delayed adaptation to darkness. 

Aliphatic acids such as butyric acid have been previously implicated as being allelopathic compounds (46, 47, 23). Chou and Patrick (23) isolated butyric acid from soil amended with rye and showed that it was phytotoxic. Hydroxy acids have also been shown to possess phytotoxic properties (48) but have not been implicated in any allelopathic associations. Since SHBA is a stereo isomer, and the enantiomer was not identified because of impurity, all bioassays were run using a racemic mixture. The D-(-) stereo isomer of SHBA has been isolated from both microorganisms and root nodules of legumes and is suspected to be a metabolic intermediate in these systems (49). It is likely that only one enantiomer was present in the extract therefore, the true phytotoxic potential of this compound awaits clarification of the phytotoxicity of the individual enantiomers. 

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