ATV has been a widely used drug in the treatment of dyslipidemia and coronary heart disease for its cholesterol-lowering efficacy. However, beyond the hypolipidemic property, recent studies have also demonstrated that ATV has neuroprotective effects as the result of anti-inflammatory, antioxidant, and immunomodulatory activities[15-17]. Meanwhile, in our previous study[7], ATV can be detected in the hematoma fluid in CSDH patients and the concentration up to 40 ng/mL, thus raising the question of whether or not ATV can penetrate the blood-brain barrier (BBB). A hematoma is an encapsulated collection of fluid, blood, and blood degradation products layered between the arachnoid and dura mater. Moreover, it may create functional disruption of the BBB in CSDH patients[18, 19], which suggests that ATV in hematoma fluid may derive from CSF or blood. In this study, our results also showed that no matter how high the concentration of ATV in plasma, the ATV level in CSF was very low, nearly equivalent to zero, which indicated that ATV in plasma can hardly cross the BBB into CSF. ATV in hematoma fluid may originate from blood rather than CSF. The pathophysiological processes involved in the formation of CSDH showed that following the pathological delamination of the dural border cells, two membranes are formed and these membranes are the source of fluid exudation and hemorrhage, which contain numerous highly permeable capillaries[19]. Leaky capillaries under inflammatory stimulation may allow ATV derived from blood across the thin wall of capillaries into the hematoma fluid.

Therefore, the effect of DXM on the pharmacokinetics of ATV was investigated and then the effect of DXM on the uptake of ATV into hepatocytes was evaluated to investigate the underlying mechanisms of how DXM increased the ATV level in plasma. Our results showed that the combination of ATV and DXM increased the AUC of ATV, o- ATV, andp- ATV in plasma by 1.550, 1.420, and 1.676 times, respectively, and inhibited the uptake of ATV into hepatocytes by 59.24%. These results suggested that DXM changes ATV disposition by increasing ATV distribution in peripheral blood, which may be beneficial for ATV anti-inflammatory activity. As is known to all, ATV is an inhibitor of HMG-CoA reductase, which is the rate-limiting enzyme in cholesterol biosynthesis and the liver is the main site of its action[20]. However, collected pieces of evidence have suggested that statins have anti-inflammatory and antioxidant properties[21-23], which could be independent of their lipid-lowering activity. Kureishi et al. showed that simvastatin induced Akt-mediated phosphorylation of endothelial nitric oxide synthase, thereby leading to NO production, and promoting endothelial cell survival in an Akt-dependent manner. Thus, Akt may function as a new biological target for statin action[21]. In vitro, statins can downregulate receptors on macrophages that take up oxidized low-density lipoprotein, thus reducing the formation of foam cells[24]. Collectively, these pieces of evidence suggested that increasing ATV distribution in peripheral blood to a safe degree may be beneficial for ATV treatment of vascular inflammatory diseases.

In addition, ATV is the substrate of CYP3A4 and OATP1B1. Inhibitors of CYP3A4 and OATP1B1 combined with ATV could increase the plasma concentration of ATV to different degrees[25]. McCune et al[26] had shown that 2–250 µmol/L DXM can result in an average 1.7–6.9-fold increase in CYP3A4 activity in hepatocytes and DXM at doses used clinically can also increase CYP3A4 activity in vivo. However, our results showed that although DXM is a CYP3A4 inducer, DXM increased the AUC of ATV in plasma. Therefore, we speculated that DXM changes the plasma concentration of ATV and its metabolites o- ATV andp- ATV, which may be related to OATP1B1. Our study first provided evidence that OATP1B1 protein expression was downregulated by DXM. Meanwhile, OATP1B1 is highly expressed in the liver and localized on the basolateral membrane of hepatocytes, which mediates the uptake of ATV from the portal vein into hepatocytes[27]. Therefore, the increased plasma concentrations of ATV and its active metabolites may be related to the inhibition of OATP1B1 by DXM. Moreover, the t_1/2of ATV and its two metabolites were prolonged by DXM, which could also be the result of less uptake of ATV into the liver when the expression of OATP1B1 was inhibited by DXM. These results were consistent with previous reports that green tea consumption enhanced hepatic CYP3A4 enzyme activity and lower OATP1B1 protein expression in rats, with an 85% and 93.3% increase in AUC_0–6h of ATV and AUC_0–6h of o- ATV[28].

LXRα is a member of the nuclear receptor superfamily and plays an important role in regulating target genes involved in drug metabolism and transport. We investigated the protein expression of LXRα and our results showed that DXM inhibited LXRα expression both in rat liver and human hepatocytes. In addition, dual-luciferase reporter assay showed that DXM inhibited OATP1B1 promoter activation via LXRα. However, whether or not DXM directly inhibited or downregulated the expression of LXRα through an intermediate substance remains to be further elucidated. In the human trophoblast cell line, DXM concentration dependently reduced the expression level of LXRα and the glucocorticoid receptor inhibitor could reverse dexamethasone-induced expression inhibitions of LXRα[29].