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Drug Interactions of Imperatorin and Curcumin on Macitentan in vitro and in vivo
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Drug Interactions of Imperatorin and Curcumin on Macitentan in vitro and in vivo
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Journal Article
Drug Interactions of Imperatorin and Curcumin on Macitentan in vitro and in vivo
2025
Overview
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.
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.
In vitro, the results indicated that imperatorin and curcumin could inhibit the metabolism of macitentan, with IC
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
, AUC
, T
, t
, and C
for macitentan while a decrease in CL
when combined with imperatorin. The metabolite ACT-132577 exhibited substantial increases in t
, T
, and C
. Combined with curcumin, the AUC
and T
of macitentan were significantly increased, while CL
was significantly decreased. Conversely, the metabolite ACT-132577 exhibited a substantial decrease in CL
, accompanied by notable increases in AUC
and T
.
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.
Publisher
Dove Medical Press Limited,Taylor & Francis Ltd,Dove,Dove Medical Press
Subject
/ Animals
/ Curcumin
/ Curcumin - administration & dosage
/ Cytochrome P-450 CYP3A - metabolism
/ Dose-Response Relationship, Drug
/ Enzymes
/ Furocoumarins - administration & dosage
/ Furocoumarins - pharmacology
/ Humans
/ Liver
/ Male
/ Microsomes, Liver - drug effects
/ Microsomes, Liver - metabolism
/ Molecular Docking Simulation
/ Plasma
/ Pyrimidines - administration & dosage
/ Pyrimidines - pharmacokinetics
/ Rats
/ Reagents
/ Sulfonamides - administration & dosage
