AUTHOR=Wei Xinyi , Su Yanding , Cheng Qian , Liang Songmao , Zhang Tingping , Duan Lengxin , Shen Xiuwei , Qiu Xiangjun 

TITLE=Herb-drug interactions of silybinin and cilofexor in beagle dogs based on pharmacokinetics by UPLC-MS/MS

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1334402

DOI=10.3389/fphar.2024.1334402

ISSN=1663-9812

ABSTRACT=<p><bold>Objective:</bold> A remarkably sensitive, accurate, and efficient ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach was developed as a facile and expeditious method for measuring cilofexor concentration in beagle dogs, the herb-drug interactions between silybinin and cilofexor was explored based on pharmacokinetics.</p><p><bold>Methods:</bold> The plasma sample protein of the beagles were rapidly sedimented with acetonitrile, and cilofexor and tropifexor (internal standard, ISTD) were separated by gradient elution using a 0.1% formic acid aqueous solution and acetonitrile as the mobile phase. The concentrations were detected using positive ion multiple reaction monitoring (MRM) mode. Mass transfer pairs were m/z 587.91→267.91 for cilofexor and m/z 604.08→228.03 for ISTD, respectively. A two-period self-controlled experimental design was adopted for the HDIs experiment. In the first period (Group A), six beagle dogs were orally administered cilofexor at a dose of 1 mg/kg. In the second period (Group B), silybinin (3 mg/kg) was orally administered to the six beagle dogs twice a day for seven consecutive days, after which cilofexor was orally administered. The cilofexor concentration in beagle dogs was determined, and HDIs were evaluated based on their pharmacokinetics.</p><p><bold>Results:</bold> The accuracy and precision of cilofexor were both less than 15%, and the recoveries, matrix effects, and stability met the relevant requirements. The C<sub>max</sub> of cilofexor in group B was 49.62% higher than that in group A, whereas the AUC<sub>(0-t)</sub> and AUC<sub>(0−∞)</sub> of cilofexor in group B were 47.85% and 48.52% higher, respectively, than those in group A. Meanwhile, the t<sub>1/2</sub> extended from 7.84 h to 9.45 h, CL and Vz decreased in Group B.</p><p><bold>Conclusion:</bold> A novel UPLC-MS/MS approach was successfully applied for the measurement of cilofexor in beagle dog plasma. Silybinin can alter the pharmacokinetics of cilofexor in beagle dogs, thereby increasing plasma exposure to cilofexor.</p>