Epimerization study of the l,l- and l,d-diastereoisomers of the calpain inhibitor MDL 28170 by capillary electrophoresis

MDL 28170, Cbz-(l)–Val-(d,l)–Phe-H, which exists as a mixture of l,l- and l,d-diastereoisomers, is a calpain inhibitor currently investigated as a novel therapeutic agent for the treatment of ischemic stroke and head and spinal trauma. This report describes a capillary electrophoresis (CE) method that uses sodium dodecyl sulfate (SDS) micellar electrokinetic conditions for the separation of the l,l- and l,d-diastereoisomers of MDL 28170. The report also describes the applications of this CE method to the study of epimerization of the l,l- and l,d-diastereoisomers in pH 7.4 phosphate buffered saline solution (PBS), rat and human plasma at 37 °C. The relative percent-time courses obtained showed interconversion of the diastereoisomers in all three matrices studied. However, the epimerization process in rat and human plasma was found to be at least 50 times faster than that in PBS. The epimerization half-life of the l,l-diastereoisomer in rat plasma was approximately 30 min, which is about three-fold faster than the observed elimination half-life of the l,l-diastereoisomer reported in a pharmacokinetic study following intravenous bolus dosing.