In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animalspecies and man

The objectives of this study were to investigate the protein binding and th e in vitro hydrolysis rate of clevidipine and its enantiomers in the rat, d og and man in different biological matrices including blood and plasma from volunteers with deficient pseudocholinesterase activity. The in vitro half -life in blood was 0.6 min (rat), 15.7 min (dog) and 5.8 min in man with no rmal pseudocholinesterase activity, while the half-life was approximately 9 min in blood from pseudocholinesterase deficient volunteers. The half-life in pseudocholinesterase deficient volunteers was prolonged, although the h ydrolysis rates in blood and red blood cells (RBC) were much higher than in plasma, suggesting that esterases located in the RBC are most important in the blood metabolism of clevidipine. A decrease in temperature increased t he half-life of clevidipine in blood, whereas dilution of the blood did not affect the in vitro half-life of clevidipine. The albumin concentration af fected the hydrolysis rate of clevidipine in RBC suspended with saline. The protein binding of clevidipine and its enantiomers was >99.5% in plasma fr om all species studied. There was a difference between the free fractions o f S- and R-clevidipine in man, 0.43 and 0.32%, respectively, and this stere oselective binding might be the reason for the 10% difference between the i n vitro hydrolysis rates of the enantiomers in human blood. (C) 1999 Elsevi er Science B.V. All rights reserved.