Study On The Absorption Of PEPT1 Based Modified Valsartan Compounds

ObjectivesStudy the absorption of valsartan and its modified compounds in the small intestine, by using single pass perfusion technique. And study the vivo absorption of the compounds, which have a better intestinal absorption than valsartan, obtain their pharmacokinetic parameters to provide the basis for the further development of new drugs.Methods1. Adsorption of valsartan and its modified compounds in the small intestine of ratsSingle pass intestinal perfusion experiments in rat's small intestine were performed to calculate the absorption rate constant (Ka) and intestinal permeability (Papp) of valsartan and its modified compounds, and UV and HPLC-UV methods were used to determine the content of phenol reds and the compounds.2. Vivo absorption experimentsEighteen Sprague-Dawley rats (male and female) were fasted for 12 h (free access to water) before the experiment. VST,VST-Gly-OMe and VST-Gly-OEt mixed with CMC-Na (0.5 g/L) were given to the rats by oral administration,20mg/kg.150μL whole blood was collected from ophthalmic vein plexus at 0 (pre-dose,and several time point within 16 h post-administration. High-performance liquid chromatography coupled with Fluorescence Detector were used to determine VST,VST-Gly-OEt and VST-Gly-OMe in plasma. Pharmacokinetic parameters of VST,VST-Gly-OEt,VST-Gly-OMe were calculated with DAS version 2.0.Results1. Results of intestinal perfusionThe absorption rate constant (Ka×103min-1) of VST,VST-OMe,VST-Gly-OMe,VST-Gly-OH,VST-Gly-OEt,VST-Gly-Gly-OMe, VST-Gly-Gly-OH,VST-Glu-OMe,VST-Glu-OH,VST-Gly-Ala-OMe,VST-Gly-Ala-OH,VST-Phe-OMe,VST-Phe-OH,VST-Ala-OMe,VST-Ala-OH in low concentration Perfusion test are 0.95±0.39,10.49±3.59,6.52±1.72,1.19±0.30,9.53±3.26,2.88±0.61,0.86±0.14,13.15±3.02,2.02±0.70,4.41±1.39,9.46±2.20,16.47±3.82,2.59±0.65,13.39±0.86,2.69±0.92; and their intestinal permeability (Papp×105cms-1) are 12.39±5.03,186.29±83.91,96.44±30.04,14.13±3.96,161.12±72.00,38.66±8.77,6.70±4.74,129.37±36.99,16.62±5.71,38.26±11.54,85.84±23.12.166.60±50.97,21.72±6.76,137.26±29.08,25.01±13.06 respectively. Their absorption rate constant (Ka×103 min-1) in high concentration Perfusion test are 2.20±0.38,16.58±3,11.51±1.43,2.63±0.43,13.80±2.61,4.68±0.56,2.24±0.48,9.25±2.32.1.82±0.39,3.77±1.26,7.33±2.49,14.59±1.67,2.58±0.36,10.13±0.72,2.09±0.51,and their intestinal permeability (Papp×105 cms-1) are 16.57±2.69,173.46±57.22,101.57±14.93,20.41±3.45,129.84±31.31,37.54±4.72,17.35±3.76,81.87±21.40,11.63±2.53,32.95±14.47,75.19±24.36,136.76±25.90,16.77±2.41,95.73±9.20,16.22±4.06 respectively.2. Results of vivo absorption testThe Pharmacokinetic parameters of VST are:tmax:0.53±0.19 h, t1/2: 3.18±0.74h, Cmax:10.08±2.45μmol/L, AUC(0-t):42.90±6.22μmol/L·h, AUC(0-∞):45.76±6.39μmol/L·h; V-Gly-OMe was hydrolyzed to VST-GLY-OH, and its Pharmacokinetic parameters are:tmax:0.33±0.15 h, t1/2:3.32±1.30h, Cmax:7.16±2.52μmol/L, AUC(0-t):20.52±6.41μmol/L·h, AUC(0-∞):21.93±7.40μmol/L·h; V-Gly-OEt was hydrolyzed to VST-GLY-OH, and its Pharmacokinetic parameters are:tmax: 0.36±0.16h, t1/2:4.63±0.77 h, Cmax:7.52±2.12μmol/L, AUC(0-t): 20.96±6.47μmol/L·h, AUC(0-∞):22.52±7.37μmol/L·h.Conclusion1. The absorption ability of VST-OMe,VST-Gly-OMe,VST-Gly-OEt,VST-Gly-Gly-OMe,VST-Glu-OMe,VST-Gly-Ala-OMe,VST-Gly-Ala-OH,VST-Phe-OMe,VST-Ala-OMe in intestinal was higher then VST. 2. From statistical Analyses of pharmacokinetic parameters, we can see that AUC(0-t),AUC(0-∞)of VST-Gly-OMe and VST-Gly-OEt were significantly smaller than that of VST. But t1/2 of VST-Gly-OEt is longer than VST's.