Figure 1. The representative chromatograms of ATV (A),o- ATV (B), p- ATV (C), d5-ATV (D), and RSV (E) in rat plasma. Abbreviations: ATV, atorvastatin; o- ATV, o- hydroxy atorvastatin;p- ATV, p- hydroxy atorvastatin; d5-ATV, d5-atorvastatin; RSV, rosuvastatin.

Figure 2. Plasma concentration-time profiles of ATV (A),o- ATV (B), and p- ATV (C) in rat plasma. Atorvastatin calcium (0.27 mg/100 g) and dexamethasone acetate (0.02 mg/100 g) were orally administered to rats for a single dose. Values at each time point are expressed as the mean ± SD (n = 6). Abbreviations: ATV, atorvastatin; o- ATV, o- hydroxy atorvastatin;p- ATV, p- hydroxy atorvastatin.

Figure 3. The concentration of ATV in plasma and CSF.

A: Valley concentration of ATV in plasma and CSF (n = 8). ATV (PLASMA vs CSF, Unpaired t-test, **P = 0.0060), ATV+DXM (PLASMA vs CSF, Mann-Whitney U test, *P = 0.0200), PLASMA (ATV vs ATV+DXM, Unpaired t-test, P = 0.3213); B: Peak concentration of ATV in plasma and CSF (n = 5). ATV (PLASMA vs CSF, Mann-Whitney U test, **P = 0.0079), ATV+DXM (PLASMA vs CSF, Unpaired t test, *P= 0.0150), PLASMA (ATV vs ATV+DXM, Unpaired t test, *P = 0.0275). The values are given as mean ± SD. Abbreviations: ATV, atorvastatin; DXM dexamethasone; CSF, cerebrospinal fluid.

Figure 4. DXM inhibited the expression of OATP1B1 and LXRα in rat liver.

A: Expressions of OATP1B1 were analyzed by Western blot assay; B: The protein expression quantification of OATP1B1 (Tukey’s multiple comparisons test, Control vs. DXM, *P = 0.0436; ATV vs. ATV+DXM, **P = 0.0066); C: Expressions of LXRα was analyzed by Western blot assay; D: The protein expression quantification of LXRα (Tukey’s multiple comparisons test, Control vs. DXM, ***P = 0.0005; ATV vs. ATV+DXM, **P = 0.0038). The values are given as mean ± SD (n = 6). Abbreviations: ATV, atorvastatin; DXM dexamethasone; OATP1B1, organic anion transporting polypeptides 1B1; LXRα, liver X receptor α.

Figure 5. DXM decreased the ATV uptake and inhibited OATP1B1 and LXRα expressions in HepG2 cells. A: Cytotoxicity of 100 nM ATV and 400 nM DXM on HepG2 cells was measured using the Cell Counting kit-8; B: The uptake of ATV by HepG2 cells after treated with 400 nM DXM (Unpaired t-test, ATV vs. ATV+DXM, **P = 0.0011); C: OATP1B1 and LXRα expressions were analyzed by Western blot assay; D: The protein expression quantification of OATP1B1 (Tukey’s multiple comparisons test, ATV vs. DXM, *P = 0.0262; ATV vs. ATV+DXM, *P = 0.0339); E: The protein expression quantification of LXRα (Tukey’s multiple comparisons test, Control vs. DXM, *P = 0.0167; ATV vs. ATV+DXM, *P = 0.0290). The values are given as mean ± SD (n = 3). Abbreviations: ATV, atorvastatin; DXM dexamethasone; OATP1B1, organic anion transporting polypeptides 1B1; LXRα, liver X receptor α.

Figure 6. DXM inhibited OATP1B1 promoter activation via LXRα. Renilla reporter activity was used as an internal control. Values were normalized for those in the empty plasmid transfected cells and were expressed relative to that in the control. (one-way ANOVA, 0.1%DMSO vs. GW3965, ****P < 0.0001; 0.1%DMSO vs. DXM, ***P= 0.0003; GW3965 vs. DXM+GW3965, ****P < 0.0001). The values are given as mean ± SD (n = 3). Abbreviations: DXM dexamethasone; OATP1B1, organic anion transporting polypeptides 1B1; LXRα, liver X receptor α; GW3965, LXRα agonist.