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Feifei Chen,1,* Hui Jiang,1,* Jia Xu,1 Shuanghu Wang,1 Deru Meng,1 Peiwu Geng,1 Dapeng Dai,2 Quan Zhou,1 Yunfang Zhou1 1The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, Zhejiang 323000, People’s Republic of China; 2The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, People’s Republic of China*These authors contributed equally to this work.Correspondence: Yunfang Zhou; Quan ZhouThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, Zhejiang 323000, People’s Republic of ChinaTel/Fax +86 578 2780081Email zyf2808@lsu.edu.cn; zhouquan1991@lsu.edu.cnPurpose: The purpose of the present study was to investigate the effects of vonoprazan on the pharmacokinetics of venlafaxine in vitro and in vivo.Methods: The mechanism underlying the inhibitory effect of vonoprazan on venlafaxine was investigated using rat liver microsomes. In vitro, the inhibition was evaluated by determining the production of O-desmethylvenlafaxine. Eighteen male Sprague–Dawley rats were randomly divided into three groups: control group, vonoprazan (5 mg/kg) group, and vonoprazan (20 mg/kg) group. A single dose of 20 mg/kg venlafaxine was administrated to rats orally without or with vonoprazan. Plasma was prepared from blood samples collected via the tail vein at different time points and concentrations of venlafaxine and its metabolite, O-desmethylvenlafaxine, were determined by ultra-performance liquid chromatography-tandem mass spectrometry.Results: We observed that vonoprazan could significantly decrease the amount of O-desmethylvenlafaxine (IC50 = 5.544 μM). Vonoprazan inhibited the metabolism of venlafaxine by a mixed inhibition, combining competitive and non-competitive inhibitory mechanisms. Compared with that in the control group (without vonoprazan), the pharmacokinetic parameters of venlafaxine and its metabolite, O-desmethylvenlafaxine, were significantly increased in both 5 and 20 mg/kg vonoprazan groups, with an increase in MRO-desmethylvenlafaxine.Conclusion: Vonoprazan significantly alters the pharmacokinetics of venlafaxine in vitro and in vivo. Further investigations should be conducted to check these effects in humans. Therapeutic drug monitoring of venlafaxine in individuals undergoing venlafaxine maintenance therapy is recommended when vonoprazan is used concomitantly.Keywords: gastroduodenal ulcer, gastroesophageal reflux disease, proton pump inhibitors, vonoprazan fumarate

Yunfang Zhou,1,* Ailian Hua,2,* Quan Zhou,1 Peiwu Geng,1 Feifei Chen,1 Lianhe Yan,1 Shuanghu Wang,1 Congcong Wen3 1The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, Zhejiang 323000, People’s Republic of China; 2Department of Pharmacy, The First People’s Hospital of Yuhang District, Hangzhou, Zhejiang 311100, People’s Republic of China; 3Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang 325027, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuanghu WangThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui 323000, Zhejiang, People’s Republic of ChinaEmail wangshuanghu@lsu.edu.cnCongcong WenLaboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang 325027, People’s Republic of ChinaTel/ Fax +865782780081Email bluce494949@163.comPurpose: The aim of the present study was to investigate the interactions of the main components of Lygodium root (ie, p-coumaric acid, acacetin, apigenin, buddleoside and Diosmetin-7-O-β-D-glucopyranoside) with cytochrome P450 3A enzyme activity both in vitro and in vivo.Methods: In vitro inhibition of drugs was assessed by incubating rat liver microsomes (RLMs) with a typical P450 3A enzyme substrate, midazolam, to determine their 50% inhibitory concentration (IC50) values. For the in vivo study, healthy male Sprague Dawley rats were consecutively administered acacetin or apigenin for 7 days at the dosage of 5 mg/kg after being randomly divided into 3 groups: Group A (control group), Group B (acacetin group) and Group C (apigenin group).Results: Among the five main components of Lygodium root, only acacetin and apigenin showed inhibitory effects on the cytochrome P450 3A enzyme in vitro. The IC50 values of acacetin and apigenin were 58.46 μM and 8.20 μM, respectively. Additionally, the in vivo analysis results revealed that acacetin and apigenin could systemically inhibit midazolam metabolism in rats. The Tmax, AUC(0-t) and Cmax of midazolam in group B and group C were significantly increased (P< 0.05), accompanied by a significant decrease in Vz/F and CLz/F (P< 0.05).Conclusion: Acacetin and apigenin could inhibit the activity of the cytochrome P450 3A enzyme in vitro and in vivo, indicating that herbal drug interactions might occur when taking Lygodium root and midazolam synchronously.Keywords: Lygodium root, drug–drug interactions, rat liver microsomes, midazolam, metabolism

Background: Modern pharmacological studies show that rhizoma coptidis has protective effects on the liver, gallbladder, kidney, cerebral ischemia-reperfusion, local hypoxia injury, antiinflammatory, bone injury, nerve cells and myocardial cells. The effective components have been isolated from picroside I, II, III and IV. Introduction: A selective and sensitive ultra-performance liquid chromatography electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed for the simultaneous quantitative determination of picroside I, II, III and IV in rat plasma to aid the pharmacokinetics studies. Method: Sprague-Dawley (SD) rats were orally administered with 10 mg/kg, intravenously injected with 1 mg/kg for the mixture of picroside I, II, III and IV. The biological samples were collected at 0.083 3 h, 0.25 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h. A UPLC BEH C18 column (2.1 mm×50 mm, 1.7 μm) was used for chromatographic separation with the mobile phase consisting of acetonitrile and 0.1% formic acid by gradient elution. The flow rate was 0.4 mL/min. Multiple reaction monitoring (MRM) transitions were m/z 491.1→147.1 for picroside I, m/z 511.1→234.9 for picroside II, m/z 537.3→174.8 for picroside III and m/z 507.3→163.1 for picroside IV in negative ion mode. Result: The inter-day precision was less than 13%, the intra-day precision was less than 15%. The accuracy ranged from 89.4% to 111.1%. Recovery was higher than 79.1%, and the matrix effect ranged from 96.2% to 109.0%. Conclusion: The sensitive, rapid and selective UPLC-MS/MS method can be applied to the pharmacokinetic study of picroside I, II, III and IV in rats.

Jiquan Shen,1,* Bo Wang,1,* Shuanghu Wang,2,3 Feifei Chen,2 Deru Meng,2 Hui Jiang,2 Yunfang Zhou,2 Peiwu Geng,2 Quan Zhou,2 Bin Liu1 1Department of Orthopaedics, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, Zhejiang 323000, People’s Republic of China; 2The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, Zhejiang 323000, People’s Republic of China; 3School of Pharmaceutical Science, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Quan ZhouThe Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui 323000, Zhejiang, People’s Republic of ChinaTel/Fax +86 578 278 0081Email zhouquan1991@lsu.edu.cnBin LiuDepartment of Orthopaedics, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui 323000, Zhejiang, People’s Republic of ChinaEmail doctorliubin@163.comPurpose: The purpose of this study was to examine the effects of voriconazole on the pharmacokinetics of vonoprazan.Methods: Fifteen Sprague-Dawley rats were randomly divided into three groups: five rats in each group, including control group, single-dose group (a single dose of 30 mg/kg of voriconazole), and multiple-dose group (multiple doses of 30 mg/(kg•day) per dose of voriconazole). Each group of rats was given an oral dose of 10 mg/kg vonoprazan 30 min after the administration of voriconazole or vehicle. After the oral administration of vonoprazan, 50 μL of blood was collected into 1.5-mL heparinized tubes via the caudal vein. The concentration of vonoprazan in plasma was quantified by ultra-performance liquid chromatography/tandem mass spectrometry. Both in vitro effects of voriconazole on vonoprazan and the mechanism of the observed inhibition were studied in rat liver microsomes.Results: When orally administered, voriconazole increased the area under the plasma concentration–time curve (AUC), prolonged the elimination half-life (t1/2), and decreased the clearance (CL) of vonoprazan; there was no significant difference between the single-dose and multiple-dose groups. Voriconazole inhibited the metabolism of vonoprazan at an IC50 of 2.93 μM and showed mixed inhibition. The results of the in vivo experiments were consistent with those of the in vitro experiments.Conclusion: Our findings provide the evidence of drug–drug interactions between voriconazole and vonoprazan that could occur with pre-administration of voriconazole. Thus, clinicians should pay attention to the resulting changes in pharmacokinetic parameters and accordingly, adjust the dose of vonoprazan in clinical settings.Keywords: cytochrome P450, drug–drug interaction, pharmacokinetic, proton pump inhibitor

Additional file 3: Table S2. The quality of WES data.