Chirality and pharmacokinetics: an area of neglected dimensionality?

Drug stereochemistry has, until relatively recently, been an area of neglected dimensionality with the development of the majority of synthetic chiral drugs as racemates. This situation has changed in recent years as a result of advances in the chemical technologies associated with the synthesis, analysis and preparative scale resolution of the enantiomers of chiral molecules. As a result of the application of these technologies the potential significance of the differential pharmacodynamic and pharmacokinetic properties of the enantiomers present in a racemate have become appreciated. Many of the processes involved in drug disposition, i.e. absorption, distribution, metabolism and excretion, involve a direct interaction with chiral biological macromolecules, e.g. transporters, membrane lipids and enzymes, and following administration of a racemate the individual enantiomers frequently exhibit different pharmacokinetic profiles and rarely exist in a 1:1 ratio in biological fluids. The magnitude of the differences between a pair of enantiomers observed in their pharmacokinetic parameters tends to be relatively modest in comparison to their pharmacodynamic properties. However, the observed stereoselectivity may be either amplified or attenuated depending on the organisational level, e.g. whole body, organ or macromolecular, the particular parameter represents. Differences in parameters involving a direct interaction between a drug enantiomer and a biological macromolecule, e.g. intrinsic metabolite formation clearance and fraction unbound, tend to be largest, and comparison of parameters reflecting the whole body level of organisation, e.g. half-life, clearance, volume of distribution, may well mask significant stereoselectivity at the macromolecular level. In spite of the recent interest in drug chirality relatively limited pharmacokinetic data are available for the enantiomers of a number of commonly used racemic drugs. Factors influencing the stereo-selectivity of drug disposition include: formulation and route of administration; in vivo stereochemical stability, both chemical and enzymatic; drug interactions, both enantiomeric and with a second drug; disease state; age; gender; race; and pharmacogenetics. As a result of such factors estimation of pharmacokinetic parameters, development of complex pharmacokinetic models and plasma-concentration-effect relationships based on 'total' drug concentrations following administration of a racemate are of limited value and potentially useless.