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

The objectives of this study were to investigate the protein binding and the in vitro hydrolysis rate of clevidipine and its enantiomers in the rat, dog 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 normal 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 hydrolysis 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 the half-life of clevidipine in blood, whereas dilution of the blood did not affect the in vitro half-life of clevidipine. The albumin concentration affected the hydrolysis rate of clevidipine in RBC suspended with saline. The protein binding of clevidipine and its enantiomers was >99.5% in plasma from all species studied. There was a difference between the free fractions of S- and R-clevidipine in man, 0.43 and 0.32%, respectively, and this stereoselective binding might be the reason for the 10% difference between the in vitro hydrolysis rates of the enantiomers in human blood. (C) 1999 Elsevier Science B.V. All rights reserved.