The Absorption Mechanism And Metabolism Research Of Valsartan Enantiomers

Valsartan is a drug for the treatment of mild to moderate essential hypertension. The process of drugs in the body including four steps including absorption, metabolism, distribution and excretion. The researches of valsartan enantiomers absorption and metabolism had not been reported. The absorption of valsartan enantiomers in Caco-2cell monolayer model and metabolism of S-valsartan were studied in our paper. In order to provide the scientific basis for clinical treatment, we clarified the differences of R-and S-valsartan absorption in the body, and the metabolism of S-valsartan in the rats.The separation and quantitation of valsartan enantiomers were performed by high-performance liquid chromatography (HPLC); the apparent permeability coefficient (Papp) and the transport rate (V) were calculated. Bi-directional transport studies demonstrated that, in the concentration range of15-800μmol/L, the S-valsartans transport rate was positively correlated with the substrate concentration in the low drug range of15-60μmol/L. The transport rate decreased with the increased substrate concentration. But R-valsartans transport rate positively correlated with the substrate concentration in the range of15-800μmol/L. So in Caco-2cells monolayer model, S-valsartan was almost by the active transport way, and R-valsartan was almost the passive transport way. The Papp of S-valsartan and R-valsartan has a significant difference P<0.05both in the absorption and efflux sides. So the stereoselectivity was existed in the R-and S-valsartan transport process. And P-glycoprotein has no effect on the R-and S-valsartan transport process. When P-gp substrate combined with valsartan enantiomers, the S-valsartan increased the efflux rate of P-glycoprotein substrate rhodamine-123, and R-valsartan reduced the efflux rate. It showed that S-valsartan could induce P-glycoprotein, and R-valsartan could inhibit P-glycoprotein.In the research of rat metabolism, HPLC-MS/MS was used to detect the fecal, urine and bile samples of rat. Three metabolites were found in rat bile.In addition to the drug prototype, we found two new metabolites, the glucuronide metabolite (M1) and ω-1eacyl-fat side chain carbonyl of metabolite (M2). After orally in rats, valsartan was excreted by three ways. And its main excretion was prototype metabolite, while a small amount of metabolites was generated.