Enantioselective pharmacokinetics of the enantiomers of clevidipine following intravenous infusion of the racemate in essential hypertensive patients

The aim of the study was to characterize the individual pharmacokinetics of (-)-R- and (+)-S-clevidipine following intravenous constant rate infusion of rac-clevidipine to essential hypertensive patients. Twenty patients rece ived three out of five randomized treatments with clevidipine. The pharmaco kinetics of the separate enantiomers were evaluated by compartmental analys is of blood concentrations vs. time curves using the population approach. T he derived pharmacokinetic parameters were used to simulate the time for 50 and 90% postinfusion decline following various infusion times of rac-clevi dipine. A two-compartment model was used to describe the dispositions of th e enantiomers; there were only minor differences between the estimated phar macokinetic parameters of the separate enantiomers. The mean blood clearanc e values of (-)-R- and (+)-S-clevidipine were 0.103 and 0.096 1/min/kg, and the corresponding volumes of distribution at steady state were 0.39 and 0. 54 1/kg, respectively. The context-sensitive half-time was approximately 2 min regardless of stereochemical configuration, and a 90% decline in concen tration was achieved approximately 8 min postinfusion for (-)-R-clevidipine and 11 min for (+)-S-clevidipine, following clinically relevant. infusion times with clevidipine. In conclusion, both enantiomers are high-clearance compounds with similar blood clearance values. The volume of distribution f or the enantiomers is slightly different, presumably due to differences in the protein binding. From a pharmacokinetic point of view, the use of a sin gle enantiomer as an alternative to the racemic clevidipine will not offer any clinical advantages. Chirality 13:130-134, 2001. (C) 2001 Wiley-Liss, I nc.