Stereoselectivity in pharmacokinetics: a general theory.
Stereoselectivity in pharmacokinetics may be characterized by a measurable difference between enantiomers in a pharmacokinetic parameter. We propose that pharmacokinetic parameters may be classified according to three levels of organization in the body and that the hybrid character of parameters increases with the level of organization that they represent. At the molecular level are intrinsic metabolite formation clearances and fraction of drug unbound in plasma, reflecting the selectivity of an endogenous macromolecule for the enantiomers of a chiral drug molecule. At the organ level, pharmacokinetic parameters represent the combined effects of stereoselectivity in each of their component parameters within an organ. As a result, these parameters are of intermediate hybrid character. Parameters with the highest degree of hybrid character describe the pharmacokinetic behavior of a drug in the whole body. The stereoselectivity associated with each of the component parameters could either amplify or dampen the resultant stereoselectivity in hybrid parameters. The hypothesis that kinetic differences between enantiomers are inversely correlated with the degree of hybrid character was examined for four drugs: warfarin, verapamil, mephenytoin, and propranolol. By classifying pharmacokinetic parameters according to both the level of organization that they characterize and their hybrid nature, it becomes possible to account for stereoselectivity in drug distribution and elimination.
Levy
R H
RH
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195.
Boddy
A V
AV
D006801:Humans; D008617:Mephenytoin / Q000493:pharmacokinetics; D008954:Models, Biological; D010599:Pharmacokinetics; D011433:Propranolol / Q000493:pharmacokinetics; D013237:Stereoisomerism; D014700:Verapamil / Q000493:pharmacokinetics; D014859:Warfarin / Q000493:pharmacokinetics
D014859:Warfarin; D011433:Propranolol; D014700:Verapamil; D008617:Mephenytoin