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. 2025 Apr 29:19:3459-3475.
doi: 10.2147/DDDT.S505960. eCollection 2025.

Drug Interactions of Imperatorin and Curcumin on Macitentan in vitro and in vivo

Hualu Wu  1 , Qian Liu  2 , Yuxin Shen  1 , He Qi  3 , Jiade Zhao  3 , Qiaoying Li  4 , Hailun Xia  1 , Ren-Ai Xu  1 , Lu Shi  1
Affiliations

Drug Interactions of Imperatorin and Curcumin on Macitentan in vitro and in vivo

Hualu Wu et al. Drug Des Devel Ther. .

Abstract

Purpose: The purpose of this study was to establish an in vitro incubation system and an in vivo model to investigate the potential kinetic interactions of macitentan with imperatorin and curcumin, and to validate the potential inhibitory mechanisms using molecular docking.

Methods: In vitro, the enzyme kinetic profile of macitentan was explored in rat liver microsomes (RLM) and human liver microsomes (HLM). Furthermore, molecular docking technique was used to study the sites of action of macitentan, imperatorin, and curcumin with CYP 3A4. In vivo, the pharmacokinetic parameters of macitentan were investigated in Sprague-Dawley (SD) rats administered the drug orally, both as a single agent and in combination with imperatorin and curcumin.

Results: In vitro, the results indicated that imperatorin and curcumin could inhibit the metabolism of macitentan, with IC50 values of 6.58 μM and 10.86 μM in RLM and 6.97 μM and 5.71 μM in HLM, respectively. And in the study of inhibition type, in RLM, the inhibition types of imperatorin and curcumin on macitentan were mixed and non-competitive, respectively; in HLM, the inhibition types of imperatorin and curcumin on macitentan were both mixed. Furthermore, additional molecular docking studies demonstrated that both imperatorin and curcumin occupied the CYP3A4 site. In vivo, the result showed significant increases in AUC(0-t), AUC(0-∞), Tmax, t1/2, and Cmax for macitentan while a decrease in CLz/F when combined with imperatorin. The metabolite ACT-132577 exhibited substantial increases in t1/2, Tmax, and Cmax. Combined with curcumin, the AUC(0-∞) and Tmax of macitentan were significantly increased, while CLz/F was significantly decreased. Conversely, the metabolite ACT-132577 exhibited a substantial decrease in CLz/F, accompanied by notable increases in AUC(0-∞) and Tmax.

Conclusion: In vitro and in vivo studies revealed that imperatorin and curcumin exhibited inhibitory effects on the metabolism of macitentan. Furthermore, molecular docking revealed that the metabolic inhibition of macitentan by imperatorin and curcumin occurred through binding to the site on CYP3A4. However, further investigation is necessary to ascertain whether this phenomenon will occur in humans.

Keywords: UPLC-MS/MS; inhibition mechanism; molecular docking; pharmacokinetics.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Schematic chemical structures of macitentan (A), ACT-132577 (B), imperatorin (C), and curcumin (D).
Figure 2
Figure 2
Representative MRM chromatograms: (A) blank plasma sample without analyte and IS; (B) blank plasma sample containing analyte and IS; and (C) rat plasma sample after oral administration of 10 mg/kg of macitentan alone.
Figure 3
Figure 3
Michaelis-Menten plots for macitentan in RLM (A) and HLM (B). V, velocity of enzyme catalysis; Km: Michaelis-Menten constant.
Figure 4
Figure 4
IC50 curves of imperatorin and curcumin on macitentan metabolism in RLM (A and B) and HLM (C and D). IC50 shift curves of imperatorin and curcumin on macitentan metabolism in RLM (E and F).
Figure 5
Figure 5
In RLM (A) and HLM (B), Lineweaver-Burk plots, Ki secondary plots and αKi secondary plots of inhibition of macitentan metabolism by different concentrations of imperatorin.
Figure 6
Figure 6
In RLM (A) and HLM (B), Lineweaver-Burk plots, Ki secondary plots and αKi secondary plots of inhibition of macitentan metabolism by different concentrations of curcumin.
Figure 7
Figure 7
Mean plasma concentration-time curves of macitentan (A and C) and its metabolite ACT-132577 (B and D) in different groups of SD rats (n = 5).
Figure 8
Figure 8
Molecular docking: (A) Binding sites of macitentan and imperatorin to CYP3A4; (B) binding sites of macitentan and curcumin to CYP3A4. (macitentan: salmon, imperatorin: cyan, curcumin: slate, and the residues are shown in gray.); (C) binding sites of midazolam and ketoconazole to CYP3A4. (midazolam: cyan, imperatorin: salmon, and the residues are shown in gray.).
Figure 9
Figure 9
Schematic representation of the distances of macitentan (A), imperatorin (B), and curcumin (C) to ferrous ions in the heme moiety in CYP3A4.
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