Stereoselective pharmacokinetic properties of drugs which are eliminated by metabolism have been extensively studied. Surprisingly no studies have been directed toward elucidating the stereoselective pharmacokinetic properties of drugs which are renally eliminated. The proposed research seeks to determine whether the renal elimination of basic drugs is stereoselective.
The specific aims of this study are (1) to determine whether stereoselective renal elimination of drugs can be demonstrated in whole animals; (2) to elucidate the pharmacokinetic mechanisms responsible for any observed stereoselective renal elimination and (3) to determine at a more molecular level whether the transport systems responsible for the renal secretion of basic drugs exhibit stereoselectivity. The proposed investigation will involve both in vivo studies in whole animals and in vitro studies in isolated plasma membrane vesicles. Three isomeric pairs will be studied including d- and 1- disopyramide, d- and 1- quinine, and d- and 1-mecamylamine. The in vivo pharmacokinetic studies will involve the administration to rats of each isomeric pair as a radiolabelled pseudoracemate, i.e., one isomer is radiolabelled and the other is unlabelled. This method will allow the renal clearance and binding to plasma proteins of both isomers to be determined separately, but under identical physiologic conditions. The in vitro studies will involve determination of Michaelis-Menten constants for the iomers in brush border and basal lateral membrane vesicles prepared from the renal proximal tubules of rats. The parallel in vivo - in vitro design will permit the direct study of the pharmacokinetic relevance of stereoselective renal elimination of drugs and the molecular mechanisms that are involved. Clinically, many drugs are administered as racemates. Knowledge of stereoselective renal elimination will enhance the rational use of racemic drugs which are renally eliminated. At a more molecular level, the structural requirements for renal transport which determine the pharmacokinetic properties of basic drugs have not been defined. Studies of stereoselectivity represent a first probe into the structural requirements of transport. These studies will eventually lead to a more sophisticated knowledge of the renal elimination of drugs.
