Chronic subdural hematoma (CSDH) is one of the most common neurological disorders and is particularly prevalent among elderly patients[1]. Surgical evacuation is often the main management for symptomatic patients or hematomas exerting a significant mass effect. Although most of the patients showed good results from surgical treatment, however, some patients had a post-operative recurrence and the recurrence rate was up to 33%[2]. The incidence of CSDH is increasing along with the continuous development of the aging society. Therefore, it is significantly important to investigate the effective non-surgical treatment of CSDH[3].

Meta-analysis comparing the effectiveness of different drug treatments in improving recurrence in patients with CSDH has shown that atorvastatin (ATV), dexamethasone (DXM), and tranexamic acid are efficient in improving recurrence in CSDH patients, and among them, ATV combined with DXM is the best intervention for CSDH[4]. One phase II randomized proof of concept clinical trial confirmed that low-dose DXM combined with ATV was more effective than ATV alone in reducing hematoma volume and improving neurological function in patients with CSDH[5]. Thus, the combination of DXM with ATV can inhibit vascular leakage caused by inflammatory reactions and avoid the long-term use of drug-induced adverse effects[6]. These studies suggested that there may have potential drug-drug interactions between DXM and ATV, which produced a synergistic effect in the treatment of CSDH.

Our previous study has demonstrated that DXM can enhance the anti-inflammatory and -angiogenic activities of ATV by increasing the ATV level in hematoma fluid and serum and by regulating the functions of macrophages[7]. However, the underlying mechanism of how DXM increases the presence of ATV in hematoma fluid and serum is still unknown. Therefore, we proposed the hypothesis that DXM increased the plasma concentration of ATV by inhibiting the expression of transporter. Organic anion transport polypeptides 1B1 (OATP1B1) is a transporter particularly expressed on the sinusoidal membrane of hepatocytes and mediates the uptake of drugs from blood into hepatocytes[8]. Meanwhile, inhibitors of OATP1B1 such as gemfibrozil can increase the plasma concentrations of ATV and its metabolites by about 1.5-fold, which suggests that OATP1B1 plays an essential role in drug-drug interactions of ATV[9]. Liver X receptor α (LXRα) regulates the transcription of OATP1B1 in liver-derived cell lines[10]. In addition, drug concentration analysis in vivo is the most direct and effective method to study drug pharmacokinetics and investigate drug-drug interactions. Meanwhile, LC-MS/MS is one of the most used analytical methods in the evaluation of ATVs for its better qualitative and quantitative capacities and higher resolution[11]. In our study, we investigated the effects of DXM on the pharmacokinetics of ATV and its active metabolites in rat plasma, and the distribution of ATV in cerebrospinal fluid and HepG2 cells based on the LC-MS/MS method for the detection of ATV and its active metabolites in rat plasma. The expression of OATP1B1 and its upstream nuclear receptors LXRα were also evaluated to investigate the underlying mechanism.