The Preclinical Pharmacokinetic Study Of Clevidipine Butyrate Injectable Emulsion

Clevidipine is an ultrashort-acting,third-generation intravenous calcium channel antagonist of the dihydropyridine class,which is used to effectively control the blood pressure through arterial-specific peripheral vasodilation in association with cardiacsurgery.Owing to its direct effect activity and ultra-short halflife,clevidipine is used for allowing precise titration to target blood pressure levels.The work of this paper were designed to study the pharmacokinetic features of clevidipine butyrate injection emulsion in dogs and rats,make an evaluation of pre-clinical parameters of pharmaeokinetics of the two injections,so as to support the pharmacokinetic study in human and provide guidance and reference for clinical application.1.Method validation for simultaneous determination of clevidipine and its primary metabolite in bloodA rapid,sensitive and simple liquid chromatography-tandem mass spectrometry(LC-MS/MS)method was developed and validated for the simultaneous determination of clevidipine butyrate and its primary metabolite clevidipine acid in dog blood and rat blood.The results for parameter validation such as specificity,linearity,lower limit of quantification(LLOQ),intra-and inter-day precision and accuracy,extraction recovery,matrix effect,and stability were within the acceptable limits.The validated method has been successfully applied to a pharmacokinetic study in rats and dogs for clevidipine butyrate injection.2.The pharmacokinetic study of clevidipine butyrate emulsion in Beagle dogsFollowing a single dose,two-way randomized crossover intravenous infusion to Beagle dogs,the blood samples were collected at different time points after administration and the concentrations of clevidipine and its primary metabolite in blood were determined by LC-MS/MS method described as above.The results indicated that the exposure levels of two kinds of preparations of clevidipine butyrate injection in dogs were quite consistent.3.The pharmacokinetic study of clevidipine butyrate emulsion in SD ratsFollowing a single intravenous injection to SD rats,the blood samples were collected at the certain time after administration and then the concentrations of clevidipine and its primary metabolite in blood were determined by the validated LC-MS/MS method.According to the results,the corresponding pharmacokinetic parameters of the metabolite of the two preparations showed no difference between the statistical tests.The dynamic characteristics of the two preparations were comparable uniformity.4.The tissue distribution study of clevidipine butyrate emulsion in SD ratsFollowing a single intravenous injection to SD rats,the concentrations in different tissues collected at different times were measured.After administration of 0.25h,4h,24h,48h,the tissue distribution characteristics of the two preparations in rats were extremely consistent.In conclude,the research showed that the pharmacokinetic features of the two clevidipine butyrate injections in dogs and rats were accordant by comparing the three aspects as described in the study above.