HPLC-MS Method For Determination Of Manidipine Concentration In Human Plasma And Its Pharmacokinetic Studies

Manidipine Hydrochloride,2-(4-(diphenylmethy)-1- piperazinylet hyl methyl-1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridine dicarboxylate,is a newly developed poten 1,4-dihydropyridine calci um antagonist having long-last activity.The plasma concentration of manidipine after oral administion in human is very low.Therefor e,a fast and sensitive analytical method for manidipine need to be developed for pharmacokinetic studies.1.To establish an HPLC-MS method,which was high sensitive,accuracy and reliability,for determining the concentrations of manidipine in human plasma and to evaluate its pharmacokinetic characteristics.A Venusil XBP-C₈ column was used to separate manidipine in plasma with a mobile phase of 5mM ammonium acetate (0.5%acetic acid)-methanol- methy1 cyanide(15;40;45,V/V)at a flow rate of 0.4ml.min^-1.Nimodipine was added to the plasma sample as an internal standard.Atmospheric pressure electronic spray ionization (AP-ESI)and ion mass spectral(m/z)of 611.7 were selected to quantify manidipine,and 441.1 for nimodipine.Results;The linear range of the standard curve of manidipine was 0.25-50ng.ml^-1,and the determination limit was 0.25ng.ml^-1.The extraction recovery of manidipine was determined by adding the three known levels of 0.5,5,25ng/ml to blank plasma.The recovery values for manidipine were 69.92～70.50%in plasma,intra-day and inter-day RSD were less than 7.76%.The method is sensitive,fast and accurate,and was suitable for therapeutic manidipine monitoring and human manidipine pharmacokinetic studies.2.The pharmacokinetic process of manidipine with protein binding rate of about 99%in human was coincidence with dounle compartment model.The main pharmacokinetics of manidipine were as follows,t_1/2 (6.673±2.826)h and(6.886±2.658)h,C_max(7.222±4.415)ng.ml^-1and (14.262±7.540)ng.ml^-1,T_max(1.667±0.326)h and(1.708±0.257) h,AUC_0～8(31.771±12.546)ng.h.ml^-1and(49.955±17.744) ng.h.ml^-1,MRT(6.470±1.040)h and(5.608±0.834)h after a single dose of 10mg and 20mg,and t_1/26.786±3.246h,AUC_ss 37.389±15.335ng.h.ml^-1,AUC_0～2437.389±15.335ng.h.ml^-1,AUC_0～840.242±15.377 ng.h.ml^-1,MRT 6.470±0.759h,T_max1.792±0.498 h,V 46.298±25.315L.kg^-1,CL 4.696±1.693L.h^-1.kg^-1, C_max7.881±4.554ng.ml^-1,C_min0.374±0.133ng.ml^-1, C_av1.558±0.639ng.ml^-1,DF 4.602±0.878 after 10mg a day for 7days, respectively.