AUTHOR=Zhou Yunfang , Meng Deru , Chen Feifei , Wu Zhengping , Wang Binglan , Wang Shuanghu , Geng Peiwu , Dai Dapeng , Zhou Quan , Qiu Weiwen 

TITLE=Inhibitory Effect of Imperatorin on the Pharmacokinetics of Diazepam In Vitro and In Vivo

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.01079

DOI=10.3389/fphar.2020.01079

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p>Diazepam is a benzodiazepine drug used to treat anxiety, insomnia, and muscle spasms. Imperatorin is a phytochemical isolated from medicinal plants and is widely used in herbal medicine. The aim of this study was to investigate the interactions between imperatorin and diazepam <italic>in vitro</italic> and <italic>in vivo</italic> and to provide evidence-based guidance for the safe clinical use of the drug.</p></sec><sec><title>Methods</title><p>In vitro inhibition of imperatorin was assessed by incubating rat liver microsomes with diazepam to determine IC<sub>50</sub> values and the type of inhibition. For <italic>in vivo</italic> assessment, six rats were pretreated with 50 mg/kg imperatorin for two weeks, six were administered saline, and a single dose of 10 mg/kg diazepam was administered orally to both groups 30 min after the administration of imperatorin.</p></sec><sec><title>Results</title><p>Imperatorin inhibited the <italic>in vitro</italic> metabolism of diazepam <italic>via</italic> the competitive mechanism of CYP450. The IC<sub>50</sub> values of imperatorin to nordazepam and temazepam were 1.54 μM and 1.80 μM, respectively. The inhibitory constant values for temazepam and nordazepam were 1.24 μM and 1.29 μM, respectively. Long-term administration of imperatorin significantly increased the AUC<sub>(0-12h)</sub>, AUC<sub>(0-∞)</sub>, and Cmax of diazepam, while Vz/F and CLz/F were decreased significantly (<italic>P</italic> &lt; 0.05). In turn, the AUC<sub>(0-12h)</sub>, AUC<sub>(0-∞)</sub>, and Cmax of nordazepam and temazepam decreased significantly, and Vz/F and CLz/F increased significantly (<italic>P</italic> &lt; 0.05).</p></sec><sec><title>Conclusions</title><p>This study demonstrates that imperatorin inhibits the metabolism of diazepam both <italic>in vitro</italic> and <italic>in vivo</italic>. These results indicated that more attention should be paid when taking diazepam together with food or herbs containing IMP, although further investigation is still needed.</p></sec>