Stereoselectivity drug metabolism

Eichelbaum M. Pharmacokinetic and pharmacodynamic consequences of stereoselective drug metabolism in man. Biochem Pharmacol 1988 37 93-6. 

B. Testa and J. M. Mayer, "Stereoselective drug metabolism and its significance in drug research," Progress. Drug. Res., 32 249-298 (1988). 

Testa, B. Mayer, J.M. Stereoselective drug metabolism and its significance in drug research. Prog. Drug Res. 1988, 32, 249-303. 

Testa, B. Conceptual and mechanistic overview of stereoselective drug metabolism. In Xenobiotic Metabolism and Disposition, Kato, R., Estabrook, R.W., Cayen, M.N., Eds. Taylor and Francis London, 1989 153-160. 

Stereoselective drug metabolism can be seen in close relation to the following issues ... 

Freitag, D.G., Foster, R.T., Coutts, R.T. et al. (1997) Stereoselective metabolism of rac-mexiletine by the fungus Cunninghamella echinulata yields the major human metabolites hydroxymethylmexiletine and p-hydroxymcx-iletine. Drug Metabolism and Disposition The Biological Fate of Chemicals, 25, 685-692. 

Abelo, A., Andersson, T.B., Antonsson, M., Naudot, A.K., Skanberg, I. and Weidolf, L. (2000) Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metabolism and Disposition, 28 (8), 966-972. 

Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible than the other to drug-metabolizing enzymes. As a result, the duration of action of one enantiomer may be quite different from that of the other. Similarly, drug transporters may be stereoselective. 

Numerous metabolic pathways involving mixed-fimction oxidases, esterases, transferases, and hydroxylases exhibit selectivity toward stereoisomeric substrates. Of all disposition differences that stereoisomers may display, the greatest stereoselectivity is expected in biotransformation, because of the specificity of metabolic enzymes and isoenzymes. The overall differences in hepatic clearance of stereoisomers reflect not only differences in intrinsic clearance (activity of drug metabolizing enzymes) for the isomers but also the steric effects of plasma protein binding and hepatic blood flow. 

The area of clinical pharmacology that first directed attention to the consequences of stereoisomerism on therapeutic and pharmacokinetics was that of drug interactions, particularly those of the anticoagulant warfarin. Not only may drug interactions be stereoselective, but there is a potential for one stereoisomer to alter the pharmacokinetics and pharmacodynamics of the other. A classical example is the interaction with achiral phenylbutazone, which inhibits the metabolism of active 5-warfarin but stimulates the metabolism of the less active R isomer. Other stereoselective drug interactions include the induced elimination of misoni-dazole by phenytoin. Phenytoin enhances the clearance of (4—)-misonidazole by 56%o, which is higher than the increase in clearance of 33%o noted for (—)-misonidazole. 

Bioreduction of ketones often leads to (he creation of an asymmetric center and. thereby, two possible stereoisomeric alcohols. " For example, reduction of acetophenone by a soluble rabbit kidney reductase leads to the enantiomeric alcohols (5)(-)- and (R)( + )-mcthylphen lcarbinol. with the (.V)(-) isomer predominating (3 1 ratio). The preferential formation of one stereoisomer over the other is termed product stereoselectivity in drug metabolism. " Mechanistically, ketone reduction involves a "hydride" transfer from the reduced nicotinamide moiety of the cofactor NADPH or NADH to (he carbonyl carbon atom of the ketone. It is generally agreed that this step proceeds with considerable stereoselectivity." Consequently, it is not surprising to find many reports of xenobiotic ketones that are i uced prefer-emi ly to a predominant stereoisomer. Often, ketone reduction yields dcohol metabolites that arc pharmacologically active. 

A number of recent studies extend the observation of stereoselectivity of drug metabolism. The inactive d-isomer of propanolol was metabolized in rats with a two-fold shorter plasma half-life than l-propanolol . The anti-inflammatory agent l-a-methylfluorene-2-acetic acid was isomerized in dogs to the d-enantiomer , thus being another example of stereospecific metabolic inversion. Whereas the individual R and S enantiomers of 15 were metabolized at similar rates, the half-life of the more active R isomer was prolonged in the racemic mixture, perhaps due to inhibition of metabolism of the R isomer by the S isomer. A similar effect was observed with the R and S enantiomers of amphetamines , which further illustrates that racemates may exhibit a biological profile different from that anticipated on the basis of the activity of the component enantiomers. 

Because many drugs contain either chiral centers, prechiral centers, or both, interest in stereochemical substrate-enzyme interactions, the stereospecificity of biotransformations, and species (and strain) differences in these parameters is increasing. Since enzymes themselves contain chiral centers, differential interaction of R and S isomers of drugs with drug metabolizing enzymes is the rule rather than the exception. Beckett reported stereoselectivity in the N-dealkylation, deamination, and formation of the nitrone and secondary hydroxylamine metabolites (+) -and (-) - N-benzylamphetamine ( ) in rabbits. Stereoselectivity has also been observed in the dealkylation of d-, 1-, and d,1-fenfluramine (22), an anorexiogenic agent. 

Vermeulen, N.P.E. and Breimer, D.D. (1983) Stereoselective drug and xenobiotic metabolism. Stereochemistry and Biological Activity of Drugs. Blackwell Scientific Publications, Oxford. 

The clinically used preparation of warfarin is racemic, but the enantiomers are not equipotent. In fact, (S)-warfarin is at least fourfold more potent as an anticoagulant than the (R)-warfarin. The difference in the activities and metabolism of the enantiomers is the key to understanding several stereoselective drug interactions. Similar stereochemical properties are noted for the other asymmetric coumarins (Fig. 31.5). In the case of acenocoumarol, the (R)-isomer is responsible for the majority of its activity. 

The two main sources of stereoselectivity in drug disposition are the circulatory proteins and enzymes in both the gastrointestinal tract and the liver. Both binding of drugs to proteins and metabolism by various isozymes are, therefore, often stereoselective. Many examples of stereoselective systemic clearance and presystemic metabolism exist (see Chapters 6 and 7). For a few classes of drugs, metabolism may include chiral inversion (see Chapter 8). This, if unidirectional, adds to the overall stereoselectivity in disposition of drugs. Bidirectional bioinversion (see Chapter 8), on the other hand, similar to chemical racemization (thalidomide, see Chapter 5), may diminish stereoselectivity. 

In drug metabolism, stereodifferentiation is the rule rather than the exception, and stereoselectivity in metabolism is probably responsible for the majority of the differences observed in enantioselective drug disposition. Stereoselectivity in metabolism may arise from differences in the binding of enantiomeric substrates to the enzyme active site and/or be associated with catalysis owing to differential reactivity and orientation of the target groups to the catalytic site [106]. As a result, a pair of enantiomers are frequently metabolized at different rates and/or via different routes to yield alternative products. 

The stereoselectivity of the reactions of drug metabolism may be classified into three groups in terms of their selectivity with respect to the... 

---