Pharmacokinetics Of Nimodipine In Beagle Dogs

Objective: The project was aimed to establish the bioanalysis method of Nimodipine in Beagle dog plasma,urine,feces homogenate and artificial CSF by using liquid chromatography with tandem mass spectrometry(LC-MS/MS),and then investigate the pharmacokinetics,excretion as well as brain penetration of Nimopine following intravenous and oral administrations to provide useful references for clinical use of Nimodipine in pet dogs with cerebrovascular diseases.Methods: 15 male Beagle dogs were adopted in the study and randomly arranged into 5 groups.The dogs were administered with 0.06 mg/kg Nimodipine Injection intravenously or 30 mg,60 mg,90 mg Nimodipine tablets orally,respectively.In each dosing group,plasma samples were collected at predose(0 h)and 0.083,0.25,0.5,1,2,4,8 and 24 h postdose.For the 60 mg dosing group,urine and feces samples were also collected at predose(-16-0 h),0-8?8-24 and 24-48 h postdose,in addition,another 3 animals were used for CSF collection only at 0.5,1,2,4,8 and 24 h postdose.The concentrations of Nimodipine in dog plasma,urine,feces and CSF were determined according to the established and validated LC-MS/MS method,and the pharmacokinetic parameters were calculated by using a non-compartmental model with the software Win Nonlin?(Version 6.2).Results: In this study,a LC-MS/MS method was successfully developed to determine the concentration of Nimodipine in Beagle dog plasma,urine,feces homogenate and artificial CSF.According to method validation,the accuracy,precision,sensitivity,specificity,recovery,matrix effect,linearity and stability,etc.all met the requirements of the guidance criteria for biosample analysis.The pharmacokinetic results showed that: 1)Following intravenous administration of Nimodipine at 0.06 mg/kg in Beagle dogs,concentrations of Nimodipine in dog plasma declined with a terminal half-life of 1.33±0.134 h.The total clearance(CL)was 2.04±0.355 l/hr/kg and the volume of distribution at steady state(Vss)was 2.49±0.568 l/kg.The area under the curve from time 0 to last time point(AUClast)and from time 0 to infinity(AUCINF)were 27.6±4.42 h*ng/ml and 30.0±4.77 h*ng/ml,respectively;2)Following oral administrations of Nimodipine at 30 mg,60 mg and 90 mg in Beagle dogs,respectively,the maximum plasma concentrations of Nimodipine were 260±84.9 ng/ml,514±260 ng/ml and 587±129 ng/ml obtained at 1.00±0.00 h,0.500±0.00 h and 0.833±0.289 h postdose,respectively.AUClast values of Nimodipine were 681±260 h*ng/ml,870±479 h*ng/ml and 1620±609 h*ng/ml,and AUCINF values were 707±285 h*ng/ml,885±485 h*ng/ml and 1677±618 h*ng/ml,respectively.Based on the dose corrected AUCINF ratio between PO 60 mg and IV 0.06 mg/kg arms,the bioavailability of Nimodipine in Beagle dogs was estimated to be 40.0±17.5 %;3)Following oral administration of Nimodipine at 60 mg in Beagle dogs,the maximum CSF concentration of Nimodipine was 5.35±2.04 ng/ml obtained at 1.00±0.00 h,terminal half-life was 2.54±0.635 h,AUClast and AUCINF in dog CSF were 17.4±12.3 h*ng/ml and 20.5±12.1 h*ng/ml,respectively.Therefore,the exposure(AUClast)of Nimodipine in dog CSF was about 1.99% of that in dog plasma;4)Following oral administration of Nimodipine at 60 mg in Beagle dogs,the extcretion rates of Nimodipine in dog urine and feces within 48 h postdose were 0.000897±0.000817 % and 11.0±8.73 %,respectively.Conclusion: A relatively fast elimination and large volume of distribution of Nimodipine was observed post intravenous administration.In addition,fast absorption and high bioavailablity was observed post oral administration,and the Cmax and AUClast values of Nimodipine were increased with the increase of dose level within the range of 30-90 mg.Moreover,Nimopidine was found to have the capacity of brain penetration post oral administration,and the parent drug was mainly excreted via feces other than urine.