Abstract
The promising benefits of salidroside (SAL) in alleviating high altitude sickness boost investigations on its pharmacokinetics and biological activity. However, the transportation and disposition process of SAL under hypoxic conditions has never been explored. The current study was proposed to investigate the pharmacokinetics of SAL in hypoxic rats and to explore the underlying mechanisms for the distinct metabolic fate of SAL under hypoxia. Pharmacokinetic studies on SAL was conducted in both hypoxic and normoxic rats. The transport properties of SAL were investigated on both hypoxic and normoxic Caco-2 monolayer models. Enzymes involved in SAL metabolism were identified and the effects of hypoxia on these enzymes were assessed by real-time PCR, western blotting analyses, and rat liver homogenate incubation. The renal clearance (CLr) of SAL, effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in both hypoxic and normoxic rats were also determined for renal function assessment. It was found that the systemic exposure of SAL in hypoxic rats was remarkably higher than that in normoxic rats. The barrier function of Caco-2 monolayer was weakened under hypoxia due to the impaired brush border microvilli and decreased expression of tight junction protein. Hepatic metabolism of SAL in hypoxic rats was attenuated due to the reduced activity of cytosolic β-glucosidase (CBG). Moreover, CLr of SAL was reduced in hypoxic rats due to the suppressed ERPF. Our findings suggest the potential need for dose-adjustment of SAL or its structural analogs under hypoxic conditions.
Highlights
Hypoxia triggers a sequence of physiological and pathological events
The enzyme activities of Lactate dehydrogenase (LDH), citrate synthase (CS) and the protein expression of hypoxia inducible factor-1a (HIF-1a) were monitored for hypoxic model validation
Since accumulating studies demonstrate that hypoxia triggers a sequence of physiological changes in vivo, it is critical to monitor the pharmacokinetic pro le of SAL in hypoxic rats with an aim for assessing its safety dose in clinical application.[1,12,13]
Summary
Hypoxia triggers a sequence of physiological and pathological events. The common causes of hypoxia include diseases, high altitude and aerospace traveling. Accumulating studies demonstrate that the pharmacokinetics of some drugs such as ibuprofen and sulfamethoxazole are altered when animals or humans are subjected to hypoxic conditions.[1] Rhodiola rosea L. is widely used in Asia and Eastern Europe for anti-hypoxia and preventing high altitude sickness.[2,3,4] Salidroside (SAL) (Fig. 1a) is reported as a major and crucial constituent accounting for the anti-hypoxic activity of Rhodiola. Our preliminary studies indicate an enhanced systemic exposure and reduced in vivo clearance of SAL in hypoxic rats when compared with that in normoxic rats. Such ndings entail subsequent mechanistic investigations on the absorption and disposition processes of SAL under hypoxia conditions
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