Mechanistic study on the pharmacokinetic process of salidroside in hypoxic rats

OBJECTIVE To investigate the effect of hypoxia on the pharmacokinetic process of salidrosidein rats and to explore its underlying mechanisms.METHODS The Caco-2 cell monolayer was exposed to 1% oxygen(O_2) concentration for 24 h to build the hypoxiccell model.The transportation mode of salidroside was investigated with the aid of this hypoxia model by detecting the apparent permeability coefficient(P app).Healthy Sprague Dawley(SD) rats were exposed to 9% O_2 for 72 h for the construction of hypoxic rat model.Liver sample was subsequently collected from the hypoxic rats with an aim to identify enzymes responsible for salidroside metabolism.The expression levels of salidroside-transporting and salidroside-metabolizing enzymes,including Sodium-dependent glucose cotransporters(SGLT1),β-glucosidase(GBA3)and sulfotransferase(SULT2A1),were thereafter detected by RT-PCR and Western blot.The metabolic activity of GBA3 and SULT2A1 was monitored by rat liver microsome incubation.In addition,the renal function of rats under hypoxia was assessed by detecting concentrations of blood urea nitrogen and creatinine.RESULTS The AUC and t1/2 values of salidroside in hypoxic rats were more than doubled,while the in vivo clearance was significantly reduced.Mechanistic study demonstrated that the Papp A-B/Papp B-A eualsto 10.3,indicating the potential active transport of salidrosile.The expression of SGLT1 and GBA3 was significantly decreased,which indicated a reduced metabolism of salidroside under hypoxia.Moreover,rat under hypoxia was found to suffer from renal dysfunction,with an abnormal value of blood urea nitrogen.CONCLUSION Due to the reduced metabolism and the abnormal renal function under hypoxia,the systemic exposure of salidroside in rats was significantly enhanced.