Substrate and product stereoselectivity in monooxygenase-mediated drug activation and inactivation

In this overview, stereoselective aspects of drug metabolism have been examined in a biochemical and pharmacodynamic perspective. From the facts and concepts presented, the conclusion to emerge is that the pharmacokinetic behaviour of mixtures of stereoisomers (e.g. racemates) is not always the simple addition of the behaviour of individual stereoisomers; as a consequence, stereoisomeric mixtures might display pharmacodynamic effects differing somewhat from those caused by the separate eutomers and distomers. In some circles, the notion of "isomeric ballast" is being mentioned with increasing regularity, leading almost fatally to the conclusion that eutomers should be purified from their distomeric ballast for therapeutic use. A number of examples discussed here show that in vitro and also in vivo, a racemate often displays a pharmacokinetic and pharmacodynamic behaviour which is not the mere addition of the behaviour of its separate enantiomers. This may seem as an additional argument for the therapeutic use of pure eutomers since a number of interactions are thus avoided. But does this imply that distomers must always be considered as detrimental ballast? Enforcing compulsory resolution of stereoisomeric mixtures, in particular racemates, would increase severalfold the cost of many drugs. This is a small price to pay if the benefit is an improved therapeutic index. But, to reword the question, would such a legislation automatically result in therapeutic benefits?