Stereoselectivity in drug metabolism

Abstract

Many chiral drugs are used as their racemic mixtures in clinical practice. Two enantiomers of a chiral drug generally differ in pharmacodynamic and/or pharmacokinetic properties as a consequence of the stereoselective interaction with optically active biological macromolecules. Thus, a stereospecific assay to discriminate between enantiomers is required in order to relate plasma concentrations to pharmacological effect of a chiral drug. Stereoselective metabolism of drugs is most commonly the major contributing factor to stereoselectivity in pharmacokinetics. Metabolizing enzymes often display a preference for one enantiomer of a chiral drug over the other, resulting in enantioselectivity. The structural characteristics of enzymes dictate the enantiomeric discrimination associated with the metabolism of chiral drugs. The stereoselectivity can, therefore, be viewed as the physical property characteristic that phenotypes the enzyme. This review provides a comprehensive appraisal of stereochemical aspects of drug metabolism (i.e., enantioselective metabolism and first-pass effect, enzyme-selective inhibition or induction and drug interaction, species differences and polymorphic metabolism).

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

“…There is precedence for enantiomers to have different relative activities against the same target, as well as different pharmacokinetic properties (Lu, 2007). For example, although the binding of the (S)-enantiomer of the myeloma drug thalidomide to cereblon is favored over the binding of the (R)-enantiomer (Fischer et al, 2014), the two enantiomers have different clearances such that the blood concentration of the (R)-enantiomer is higher (Eriksson et al, 1995(Eriksson et al, , 2001.…”

Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood

“…For many substances there is no sharp dividing line between toxic and lethal drug concentrations [25]. When a drug exists as a racemic mixture the picture is even more complicated [26][27][28]. One strategy to attack this problem is to perform a drug analysis that can separate between the different enantiomers.…”

Interactions between pyrazole derived enantiomers and Chiralcel OJ: Prediction of enantiomer absolute configurations and elution order by molecular dynamics simulations

“…The two enantiomers of a drug, such as thalidomide and ibuprofen [2,3], are different in pharmacological activity, acute and chronic toxicity, receptor selectivity, metabolism and excretion rate [4][5][6][7][8]. However the separation of enantiomers and confirmation of their absolute configurations is a long-standing problem [9].…”