Pharmacokinetics Of Hydrochlorothiazide Groups

1. The population pharmacokinetics of Hydrochlorothiazide in hypertensive patients in Northeast ChinaObjective:To develop and validate a LC-MS/MS method for determination of hydrochlorothiazide concentration in hypertensive patients plasma in Northeast China and to study pharmacokinetics of hydrochlorothiazide in patients. Population pharmacokinetics model and parameters were estimated by the nonlinear mixed effects model (NONMEM) program, The goal of this study is to investigate the population pharmacokinetics(PPK) of oral hydrochlorothiazide in northern Chinese patients and to identify possible relationship between covariates and population parameters.Method:A sensitive and specific high-peformance liquid chromatography/electrospray ionization tandem mass spectrometric(LC-MS/MS) method was developed and validated for the quantification of hydrochlorothiazide in human plasma. Hydrochlorothiazide was detected in negative ionization by multiple reactions monitoring with a mass spectrometer. A XTerra(?)MS C18(50×2.1 mm I.D.,5μm)column with a mobile phase composed of methanol-water (consisted of 2%ammonia) in the ratio 80:20 (v/v) was used in separation. The analytes were extracted from the matrixes with aether:dichlormethane (7:3) by liquid-liquid extraction. The calibration curve of hydrochlorothiazide in plasma have a good linear between 1.0-200ng-mL-1 (r= 0.992). The intra-day precision were 5.74%,3.28% and 3.19%, respectively. The inter-day precision were 13.9%,6.69% and 13.4%, and the accuracy (RE) were-3.92%,-12.0% and-1.91%, respectively. The recovery of extraction was more than 57%.Result:A single oral dose of 25mg hydrochlorothiazide were administrated to hypertensive patients in northern China. The final population model calculated PPK of hydrochlorothiazide parameters: (CL,/F)i= 78.1·0.785 GEND-0.583(HR/76 5)·Exp (ηCLl1) (L·h-1) (CL2/F)i=33.7·Exp(ηcL2i) (L·h-1) (V1/F)i=226·EXP(ηV1i) (L) (V2/F),=438·EXP(ηV2i) (L) (Ka) i= 0.322·1.49 ((2-VGTB) (3-VGTB)/2·(4-VGTB)/3) Exp (ηKAi) (h-1)GEND,HR and VGTB are Gender, heart rate and Vegetable amount of intake, respectively. Conclution:The typical values of CL1(clearance of central compartment), CL2(clearance of peripheral compartment),V1/(central volume),V2(peripheral volume), Ka were 78.1,33.7, 226,438,0.322 respectively. Gender, heart rate had statistic influence on CL1 and Vegetable amount of intake had statistic influence on Ka(P<0.01). All the Population pharmacokinetics parameters and variability can be estimated by NONMEM and provide gist for the indivilized drug administration.2. The pharmacokinetics of Hydrochlorothiazide in ratObjective:To establish a LC-MS/MS method for determination of hydrochlorothiazide in rat plasma and to study pharmacokinetics of hydrochlorothiazide for only hydrochlorothiazide, hydrochlorothiazide+nitrendipine and hydrochlorothiazide+captopril.Method:Chromatographic separation was performed at 20℃on a XTerra(?)MS C18-column (50 mm×2.1 mm,5μm, Waters). The mobile phase consisted of a mixture of methanol-water containing 2% ammonia (85:15, v/v) at a flow rate of 0.25ml/min. Liquid-liquid extraction was used to pretreat plasma sample. The calibration curve in plasma was linear between 5.0-500ng-mL-1 (r= 0.993). Accuracy and precision of method were as follows:The intra-day precision of QC samples were 4.11%,2.41% and 2.81%, respectively; the inter-day precision were 8.75%,7.21% and 4.12%, respectively; and the accurate (RE) was 2.51%,3.03% and-5.75%, respectively. The recovery of extraction of hydrochlorothiazide and internal standard indapamide were more than 68%.Result:A single oral dose of 2.25mg-kg-1 hydrochlorothiazide(A group), combination of nitrendipine and hydrochlorothiazide(B group) and combination of captopril and hydrochlorothiazide(C group) in rat. Main pharmacokinetic parameters for A, B and C were as follows:Tmax were 1.50±0.35,1.40±0.42 and 1.20±0.57 h; Cmax were 120±16.8,241±98.6 and 295±24.1 ng-mL-1; t1/2 were 2.69±0.14,3.05±0.54 and 3.21±1.34 h; Cl/F were 13.2±18.2, 12.7±0.80 and 16.8±15.1 mL-h-1·kg"1; AUC0-t were 469±42.2,964±347 and 715±269 ng-h-mL"1 for the test drugs, respectively.Conclution:The developed LC-MS/MS method is proved to be superior in simple, sensitive and efficient. The results showed the plasma concentration of B group and C group was significantly higher than alone hydrochlorothiazide, but three groups of mean time to peak were approximately same, about 1.5h. The pharmacokinetics parameters of hydrochlorothiazide had a series of changes after combination of nitrendipine and hydrochlorothiazide and combination of captopril and hydrochlorothiazide in rat. 3. The pharmacokinetics of Hydrochlorothiazide in miceObjective:To establish a LC-MS/MS method for determination of hydrochlorothiazide in mice tissue and to study pharmacokinetics and tissue distribution of hydrochlorothiazide.Method:Chromatographic separation was performed at 20℃on a Restek Pinnacle C18-column (50 mm X 2.1 mm,5um, Waters). The mobile phase consisted of a mixture of methanol-water containing 2% ammonia (90:10, v/v) at a flow rate of 0.30ml/min. Liquid-liquid extraction was used to pretreat tissue sample. The calibration curve in tissue was linear between 0.05-50μg-g-1 (r= 0.999). Accuracy and precision of method were as follows:The intra-day precision of QC samples were 9.91%,5.73% and 4.84%, respectively; the inter-day precision were 9.16%,4.67% and 7.41%, respectively; and the accurate (RE) was 5.02%,0.60% and 8.25%, respectively. The recovery of extraction of hydrochlorothiazide and internal standard ibuprofen were more than 65%.Result:A single oral dose of 6.5mg-kg-1 hydrochlorothiazide in mice. Main pharmacokinetic parameters for heart, liver, kidney, stomach and intestine were as follows:Tmax were 1.20±0.27,1.00±0.35,0.80±0.27,0.50±0.00 and 1.00±0.00 h; Cmax were 4.75±0.32,10.94±0.89,35.49±3.63,20.75±2.39 and 42.44±4.71μg-g-1, respectively.Conclution:The developed LC-MS/MS method is proved to be superior in simple, sensitive and efficient. The results showed hydrochlorothiazide in the stomach and intestine rapid absorption,Tmax were 0.5 h and 1.0 h, respectively. After the drug enters stomach and intestines, enters blood rapidly, then distributes in each tissue, including the highest levels of intestinal, the the lowest of heart. This experiment to further study the hydrochlorothiazide in vivo metabolism, the clinical reasonable rational drug use provides the reference and the theory basis.