缬沙坦大鼠在体肠吸收动力学

In situ intestinal absorption kinetics of valsartan in rats

通过大鼠在体单向肠灌流模型(SPIP),采用反相高效液相色谱法测定大鼠肠液中缬沙坦的浓度,研究缬沙坦的肠吸收动力学与P-糖蛋白(P-gp)和有机阴离子转运多肽(OATP)对缬沙坦肠吸收的影响。结果表明,缬沙坦为全肠段吸收,吸收速率与灌流液的pH和肠段部位有关,吸收速率按十二指肠、空肠、结肠和回肠顺序下降。缬沙坦在十二指肠的非线性吸收动力学参数为Ka=0.328 h-1;Vm=72.652μmol/(L.h);Km=10.968μmol/L;Vms=69.115μmol/(L.h);Kms=0μmol/L。空肠、结肠和回肠的吸收速率常数分别为(0.595±0.091),(0.586±0.153)和(0.551±0.030)h-1。与原药组相比,含P-gp抑制剂药物组Papp显著增加,含OATP抑制剂药物组Papp显著减少(P<0.05)。缬沙坦的肠吸收机制为主动转运-被动扩散混合吸收,符合非线性动力学过程。

The aim of this study was to investigate the absorption mechanism of valsartan in various intestinal segments.Single-pass intestinal perfusion（SPIP） model was used to study the intestinal absorption kinetics of valsartan and the effects of drug transporters,including P-glycoprotein（P-gp） and organic anion transporting polypeptide（OATP）,on in situ intestinal absorption at different segments in rats.Valsartan was assayed by RP-HPLC.Valsartan was absorbed in the whole intestine,and its absorption rate of valsartan was influenced by the pH of the perfusion solution and intestinal segments.The absorption rate was descended as the order of duodenum,jejunum,colon and ileum.Valsartan absorption can be described best by nonlinear dynamic absorption parameters（Ka=0.328 h-1;Vm=72.652 μmol/（L ·h）;Km=10.968 μmol/L;Vms=69.115 μmol/（L ·h）;Kms=0 μmol/L）.The absorption rate constants（Ka） in jejunum,colon and ileum were estimated to be（0.595±0.091）,（0.586±0.153） and（0.551±0.030） h-1,respectively.Group containing P-gp inhibitor had marked increased of Papp,while for OATP inhibitor,Papp was significantly decreased（P0.05）.In conclusion,the intestinal absorption mechanism of valsartan was demonstrated to be the combination of active transport and passive diffusion,according with the nonlinear kinetics.