The use of physiologically based models to simulate enantioselective differences in pharmacokinetics

The majority of synthetic drugs are chiral and are usually administered as racemates. However, body proteins can recognize the steric configuration, and the pharmacological activity and pharmacokinetics of enantiomers usually differ. The key parameters that determine the overall enantioselectivity in disposition are those quantifying protein binding and biotransformation of drugs. Physiologically based models (PBMs) are effectively applied to predict pharmacokinetics of drugs using those parameters. In this work we used PBM to evaluate a range of changes in the model-independent pharmacokinetic parameters (total clearance, mean residence time, volume of distribution, half-life) with changing relative fraction of enantiomers unbound in the blood (range 1-8) and relative intrinsic hepatic clearance (range 1-10). A pharmacokinetic interaction between enantiomers was also simulated and it was shown that experiments with separate administration of pure enantiomers and of a racemate are equally important to avoid biases in pharmacokinetic parameter estimates due to interactions between enantiomers. Concentration-effect relationships were analyzed for the case of one enantiomer being active, and it was demonstrated that hysteresis as well as proteresis may appear depending on the differences in hepatic intrinsic clearances of enantiomers or fractions unbound in blood. The great predictive potential of physiologically based models in stereopharmacokinetics was thereby demonstrated.