Publications by authors named "Shuanghu Wang"

56 Publications

Biodegradability of Micro/Nanomotors: Challenges and Opportunities.

Adv Healthc Mater 2021 May 6:e2100335. Epub 2021 May 6.

School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China.

Micro/nanomotors (MNMs) are miniature machines that can convert chemical or external energy into their own mechanical motions. In previous decades, significant efforts have been made to improve the performance of MNMs. For practical applications, the biodegradability of MNMs is an important aspect that must be considered, particularly in the biomedical field. In this review, recent progress in the biodegradability of MNMs and their potential applications are summarized. Different biodegradable materials, including metals and polymers, or other strategies for the fabrication of MNMs, are presented. Current challenges and future perspectives are also discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.202100335DOI Listing
May 2021

Effects of dacomitinib on the pharmacokinetics of poziotinib and .

Pharm Biol 2021 Dec;59(1):457-464

The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, China.

Context: Dacomitinib and poziotinib, irreversible ErbB family blockers, are often used for treatment of non-small cell lung cancer (NSCLC) in the clinic.

Objective: This study investigates the effect of dacomitinib on the pharmacokinetics of poziotinib in rats.

Materials And Methods: Twelve Sprague-Dawley rats were randomly divided into two groups: the test group (20 mg/kg dacomitinib for 14 consecutive days) and the control group (equal amounts of vehicle). Each group was given an oral dose of 10 mg/kg poziotinib 30 min after administration of dacomitinib or vehicle at the end of the 14 day administration. The concentration of poziotinib in plasma was quantified by UPLC-MS/MS. Both effects of dacomitinib on poziotinib and the mechanism of the observed inhibition were studied in rat liver microsomes and human liver microsomes.

Results: When orally administered, dacomitinib increased the AUC, and decreased CL of poziotinib ( < 0.05). The IC values of M1 in RLM, HLM and CYP3A4 were 11.36, 30.49 and 19.57 µM, respectively. The IC values of M2 in RLM, HLM and CYP2D6 were 43.69, 0.34 and 0.11 µM, respectively, and dacomitinib inhibited poziotinib by a mixed way in CYP3A4 and CYP2D6. The results of the experiments were consistent with those of the experiments.

Conclusions: This research demonstrates that a drug-drug interaction between poziotinib and dacomitinib possibly exists when readministered with poziotinib; thus, clinicians should pay attention to the resulting changes in pharmacokinetic parameters and accordingly, adjust the dose of poziotinib in clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13880209.2021.1914114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079061PMC
December 2021

Correction: A mitochondria-targeted dual-functional aggregation-induced emission luminogen for intracellular mitochondrial imaging and photodynamic therapy.

Biomater Sci 2021 Apr;9(8):3171

The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.

Correction for 'A mitochondria-targeted dual-functional aggregation-induced emission luminogen for intracellular mitochondrial imaging and photodynamic therapy' by Yujie Zhang et al., Biomater. Sci., 2021, 9, 1232-1236, DOI: 10.1039/D0BM02099K.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1bm90032cDOI Listing
April 2021

Control the Neural Stem Cell Fate with Biohybrid Piezoelectrical Magnetite Micromotors.

Nano Lett 2021 Apr 13;21(8):3518-3526. Epub 2021 Apr 13.

School of Materials Science and Engineering, Sun Yat-Sen University, Guangzhou 510275, China.

Inducing neural stem cells to differentiate and replace degenerated functional neurons represents the most promising approach for neural degenerative diseases including Parkinson's disease, Alzheimer's disease, etc. While diverse strategies have been proposed in recent years, most of these are hindered due to uncontrollable cell fate and device invasiveness. Here, we report a minimally invasive micromotor platform with biodegradable helical () as the framework and superparamagnetic FeO nanoparticles/piezoelectric BaTiO nanoparticles as the built-in function units. With a low-strength rotational magnetic field, this integrated micromotor system can perform precise navigation in biofluid and achieve single-neural stem cell targeting. Remarkably, by tuning ultrasound intensity, thus the local electrical output by the motor, directed differentiation of the neural stem cell into astrocytes, functional neurons (dopamine neurons, cholinergic neurons), and oligodendrocytes, can be achieved. This micromotor platform can serve as a highly controllable wireless tool for bioelectronics and neuronal regenerative therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.nanolett.1c00290DOI Listing
April 2021

Inhibition and Induction by Poziotinib of Different Rat Cytochrome P450 Enzymes and in an Cocktail Method.

Front Pharmacol 2020 5;11:593518. Epub 2021 Jan 5.

The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, China.

Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib is currently under clinical investigation, and understanding its drug-drug interactions is extremely important for its future development and clinical application. The cocktail method is most suitable for evaluating the activity of cytochrome P450 enzymes (CYPs). As poziotinib is partially metabolized by CYPs, cocktail probes are used to study the interaction between drugs metabolized by each CYP subtype. Midazolam, bupropion, dextromethorphan, tolbutamide, chlorzoxazone, phenacetin, and their metabolites were used to examine the effects of poziotinib on the activity of cyp1a2, 2b1, 2d1, 2c11, 2e1, and 3a1/2, respectively. The experiment was carried out by using rat liver microsomes (RLMs), whereas the experiment involved the comparison of the pharmacokinetic parameters of the probes after co-administration with poziotinib to rats to those of control rats treated with only probes. UPLC-MS/MS was used to detect the probes and their metabolites in rat plasma and rat liver microsomes. The results revealed that the half-maximal inhibitory concentration values of bupropion and tolbutamide in RLMs were 8.79 and 20.17 μM, respectively, indicating that poziotinib showed varying degrees of inhibition toward cyp2b1 and cyp2c11. Poziotinib was a competitive inhibitor of cyp2b1 and cyp2c11, with Ki values of 16.18 and 17.66 μM, respectively. No time- or concentration-dependence of inhibition by poziotinib was observed toward cyp2b1 and cyp2c11 in RLMs. Additionally, no obvious inhibitory effects were observed on the activity of cyp1a2, cyp2d1, cyp2e1, and cyp3a1/2. analysis revealed that bupropion, tolbutamide, phenacetin, and chlorzoxazone showed significantly different pharmacokinetic parameters after administration ( < 0.05); there was no significant difference in the pharmacokinetic parameters of dextromethorphan and midazolam. These results show that poziotinib inhibited cyp2b1 and cyp2c11, but induced cyp1a2 and cyp2e1 in rats. Thus, poziotinib inhibited cyp2b1 and cyp2c11 activity in rats, suggesting the possibility of interactions between poziotinib and these CYP substrates and the need for caution when combining them in clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.593518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970697PMC
January 2021

Magnesium-Based Micromotors as Hydrogen Generators for Precise Rheumatoid Arthritis Therapy.

Nano Lett 2021 03 24;21(5):1982-1991. Epub 2021 Feb 24.

Department of Medicine Ultrasonics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Hydrogen therapy is an emerging and highly promising strategy for the treatment of inflammation-related diseases. However, nonpolarity and low solubility of hydrogen under the physiological conditions results in a limited therapeutic effect. Herein, we develop a biocompatible magnesium micromotor coated with hyaluronic acid as a hydrogen generator for precise rheumatoid arthritis management. The hydrogen bubbles generated locally not only function as a propellant for the motion but also function as the active ingredient for reactive oxygen species (ROS) and inflammation scavenging. Under ultrasound guidance, the micromotors are injected intra-articularly, and the dynamics of the micromotors can be visualized. By scavenging ROS and inflammation via active hydrogen, the oxidative stress is relieved and the levels of inflammation cytokines are reduced by our micromotors, showing prominent therapeutic efficacy in ameliorating joint damage and suppressing the overall arthritis severity toward a collagen-induced arthritis rat model. Therefore, our micromotors show great potential for the therapy of rheumatoid arthritis and further clinical transformation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.nanolett.0c04438DOI Listing
March 2021

A mitochondria-targeted dual-functional aggregation-induced emission luminogen for intracellular mitochondrial imaging and photodynamic therapy.

Biomater Sci 2021 Feb;9(4):1232-1236

The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.

A mitochondria-targeted dual-functional aggregation-induced emission luminogen, TPP-TPEDCH, was rationally designed and developed for intracellular mitochondrial imaging and photodynamic therapy. TPP-TPEDCH clearly showed the movements of mitochondria at various time points. Moreover, both in vitro and in vivo results demonstrated its excellent ROS generation ability and strong antitumor activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0bm02099kDOI Listing
February 2021

Co-delivery of doxorubicin and SIS3 by folate-targeted polymeric micelles for overcoming tumor multidrug resistance.

Drug Deliv Transl Res 2021 Jan 11. Epub 2021 Jan 11.

The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China.

Multidrug resistance (MDR) is considered as a critical limiting factor for the successful chemotherapy, which is mainly characterized by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2. In this study, folate-targeted polymeric micellar carrier was successfully constructed to co-delivery of doxorubicin (DOX) and SIS3 (FA/DOX/SIS3 micelles), a specific Smad3 inhibitor which sensitizes ABCB1- and ABCG2-overexpressing cancer cells to chemotherapeutic agents. The ratio of DOX to SIS3 in polymeric micelles was determined based on the anti-tumor activity against resistant breast cells. In addition, FA/DOX/SIS3 micelles exhibited a much longer circulation time in blood and were preferentially accumulated in resistant tumor tissue. Pharmacodynamic studies showed that FA/DOX/SIS3 micelles possessed superior anti-tumor activity than other DOX-based treatments. Overall, FA/DOX/SIS3 micelles are a promising formulation for the synergistic treatment of drug-resistant tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13346-020-00895-1DOI Listing
January 2021

Discovery of Novel and Highly Potent Resorcinol Dibenzyl Ether-Based PD-1/PD-L1 Inhibitors with Improved Drug-like and Pharmacokinetic Properties for Cancer Treatment.

J Med Chem 2020 12 2;63(24):15946-15959. Epub 2020 Dec 2.

School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.

A series of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors based on the resorcinol diphenyl ether scaffold were discovered by incorporating hydrophilic moieties into the side chain and converting into the corresponding hydrochloride salt. Among these compounds, showed the highest inhibitory activity against PD-1/PD-L1 with an IC value of 9.1 nM in a homogeneous time-resolved fluorescence binding assay. Besides, promoted HepG2 cell death dose dependently in a HepG2/PD-L1 and Jurkat/PD-1 coculture cell model. Further, demonstrated significantly higher water solubility (17.61 mg/mL) and improved pharmacokinetics (, of ∼20 h and oral bioavailability of 12%) than the previous analogues. Moreover, was highly effective in suppressing tumor growth in an immune checkpoint humanized mouse model without apparent toxicity. Collectively, these results suggest that compound represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c01684DOI Listing
December 2020

In Vitro and In Vivo Rat Model Assessments of the Effects of Vonoprazan on the Pharmacokinetics of Venlafaxine.

Drug Des Devel Ther 2020 10;14:4815-4824. Epub 2020 Nov 10.

The 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.

Purpose: 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 (IC = 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 MR.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/DDDT.S276704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667002PMC
November 2020

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

Front Pharmacol 2020 16;11:01079. Epub 2020 Sep 16.

The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, China.

Background: 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 and and to provide evidence-based guidance for the safe clinical use of the drug.

Methods: In vitro inhibition of imperatorin was assessed by incubating rat liver microsomes with diazepam to determine IC values and the type of inhibition. For 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.

Results: Imperatorin inhibited the metabolism of diazepam the competitive mechanism of CYP450. The IC 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, AUC, and Cmax of diazepam, while Vz/F and CLz/F were decreased significantly ( < 0.05). In turn, the AUC, AUC, and Cmax of nordazepam and temazepam decreased significantly, and Vz/F and CLz/F increased significantly ( < 0.05).

Conclusions: This study demonstrates that imperatorin inhibits the metabolism of diazepam both and . 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.01079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525091PMC
September 2020

Effects of avitinib on the pharmacokinetics of osimertinib in vitro and in vivo in rats.

Thorac Cancer 2020 10 19;11(10):2775-2781. Epub 2020 Aug 19.

VIP Ward, Suzhou Dushuhu Public Hospital, Dushuhu Public Hospital Affiliated to Soochow University, The First Affiliated Hospital of Soochow University, Dushuhu Branch, Suzhou, Jiangsu, China.

Background: Avitinib is one type of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. The purpose of this study was to investigate the effect of avitinib on the pharmacokinetics of osimertinib, one FDA approved third-generation TIKI, both in vitro and in vivo.

Methods: The in vitro metabolic stability and inhibitory effect of avitinib on osimertinib were assessed with rat liver microsomes (RLM) to determine its IC values. For the in vivo study, 18 Sprague-Dawley rats were randomly divided into three groups: the avitinib multiple dose group (30 mg/kg avitinib once daily for seven days), the avitinib single dose group (PEG200 once daily for six days and a dose of 30 mg/kg avitinib in PEG200 on day 7) and the control group (equal amounts of PEG200 once daily for seven days). Next, all rats were given osimertinib at a dosage of 10 mg/kg. UPLC/MS-MS was used for the determination of the concentration of osimertinib in plasma.

Results: In vitro analysis revealed that the IC value of osimertinib in rat liver microsomes was 27.6 μM. When rats were pretreated with avitinib, the values of AUC and MRT of the osimertinib were increased, and its C and T were significantly extended, whereas the values of CLz/F were significantly decreased (P < 0.05).

Conclusions: Both in vitro and in vivo results demonstrated that a drug-drug interaction between avitinib and osimertinib occurred and more attention should be paid when avitinib and osimertinib are synchronously administered in clinic.

Key Points: SIGNIFICANT FINDINGS OF THE STUDY: Osimertinib is the only market available third-generation EGFR-TKI and it has been reported that some drugs could have drug-drug interactions with it.

What This Study Adds: For the first time, we systematically investigated the effect of avitinib, one newly developed third-generation EGFR-TKI, on the pharmacokinetics of osimertinib both in vitro and in vivo using a rat model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1759-7714.13587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529555PMC
October 2020

Evaluation of acacetin inhibition potential against cytochrome P450 in vitro and in vivo.

Chem Biol Interact 2020 Sep 30;329:109147. Epub 2020 Jul 30.

Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China. Electronic address:

Acacetin is a natural flavonoid that is widely distributed in plants and possesses numerous pharmacological activities. The aim of the present study was to investigate the effects of acacetin on the activities of the cytochrome P450 family members CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP2E1, and CYP3A2 in rat liver microsomes in vitro and rats in vivo to evaluate potential herb-drug interactions by using a cocktail approach. Phenacetin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and midazolam were chosen as the probe substrates. An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous detection of the probe substrates and their metabolites. In vitro, the mode of acacetin inhibition of CYP2B1, CYP2C11, and CYP2E1 was competitive, while mixed inhibition was observed for CYP1A2 and CYP3A2. The Ki values in this study were less than 8.32 μM. In vivo, the mixed probe substrates were administered by gavage after daily intraperitoneal injection with 50 mg/kg acacetin or saline for 2 weeks. The main pharmacokinetic parameters, area under the plasma concentration-time curve (AUC), plasma clearance (CL), and maximum plasma concentration (C) of the probe substrates were significantly different in the experimental group than in the control group. Overall, the in vitro and in vivo results indicated that acacetin would be at high risk to cause toxicity and drug interactions via cytochrome P450 inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cbi.2020.109147DOI Listing
September 2020

Discovery of Novel Resorcinol Dibenzyl Ethers Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction as Potential Anticancer Agents.

J Med Chem 2020 08 30;63(15):8338-8358. Epub 2020 Jul 30.

School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.

Novel small molecule compounds based on various scaffolds including chalcone, flavonoid, and resorcinol dibenzyl ether were designed and tested for their inhibitory activity against the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 (PD-1/PD-L1) pathway. Among them, compound inhibited the human PD-1/PD-L1 interaction with IC values of 12.5 nM in homogeneous time-resolved fluorescence (HTRF) binding assays. In addition, dose-dependently elevated IFN-γ production in a coculture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, displayed significant antitumor efficacy in two different mouse models of cancer (a melanoma B16-F10 tumor model and an H22 hepatoma tumor model). Moreover, H&E staining and flow cytometry data suggested that activated the immune microenvironment in the tumor, which may contribute to its antitumor effects. This work shows is a promising lead compound for further development as a new generation of small molecule inhibitors targeting the PD-1/PD-L1 pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c00574DOI Listing
August 2020

Effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats.

Pharm Biol 2020 Dec;58(1):630-635

Division of Cardiology, Internal Medicine Department, Beijing Hospital, Beijing, P.R. China.

Context: Rivaroxaban and ticagrelor are two common drugs for the treatment of atrial fibrillation and acute coronary syndrome. However, the drug-drug interaction between them is still unknown.

Objective: To investigate the effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats both and .

Materials And Methods: A sensitive and reliable UPLC-MS/MS method was developed for the determination of rivaroxaban in rat plasma. Ten Sprague-Dawley rats were randomly divided into ticagrelor pre-treated group (10 mg/kg/day for 14 days) and control group. The pharmacokinetics of orally administered rivaroxaban (10 mg/kg, single dose) with or without ticagrelor pre-treatment was investigated with developed UPLC-MS/MS method. Additionally, Sprague-Dawley rat liver microsomes were also used to investigate the drug-drug interaction between these two drugs .

Results: The (221.34 ± 53.33 691.18 ± 238.31 ng/mL) and the AUC (1060.97 ± 291.21 3483.03 ± 753.83 μg·h/L) of rivaroxaban increased significantly ( < 0.05) with ticagrelor pre-treatment. The MRT of rivaroxaban increased from 4.41 ± 0.79 to 5.97 ± 1.11 h, while the intrinsic clearance decreased from 9.93 ± 2.55 to 2.89 ± 0.63 L/h/kg (both  < 0.05) after pre-treated with ticagrelor. Enzyme kinetic study indicated that ticagrelor decreased rivaroxaban metabolic clearance with the IC value of 14.04 μmol/L.

Conclusions: Our and results demonstrated that there is a drug-drug interaction between ticagrelor and rivaroxaban in rats. Further studies need to be carried out to verify whether similar interactions truly apply in humans and whether these interactions have clinical significance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13880209.2020.1785510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470163PMC
December 2020

Effects of Voriconazole on the Pharmacokinetics of Vonoprazan in Rats.

Drug Des Devel Ther 2020 4;14:2199-2206. Epub 2020 Jun 4.

Department of Orthopaedics, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, Zhejiang 323000, People's Republic of China.

Purpose: 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 (t), 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/DDDT.S255427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280087PMC
March 2021

Pharmacokinetics of Lusutrombopag, a Novel Thrombopoietin Receptor Agonist, in Rats by UPLC-MS/MS.

Int J Anal Chem 2020 30;2020:7290470. Epub 2020 May 30.

Department of Pharmacy, The First People's Hospital of Wenling, Wenling 317500, Zhejiang, China.

Lusutrombopag is a second oral thrombopoietin (TPO) receptor agonist that selectively acts on human TPO receptors. In the study, UPLC-MS/MS was used to establish a selective and sensitive method to determine lusutrombopag with poziotinib as IS (internal standard) in rat plasma. Samples were prepared by precipitating protein with acetonitrile as a precipitant. Separation of lusutrombopag and poziotinib was performed on a CORTECS UPLC C18 column (2.1 ∗ 50 mm, 1.6 m). The mobile phase (acetonitrile and water containing 0.1% formic acid) with gradient elution was set at a flow rate of 0.4 ml/min. The mass spectrometric measurement was conducted under positive ion mode using multiple reaction monitoring (MRM) of / 592.97 ⟶ 491.02 for lusutrombopag and / for poziotinib (IS) 492.06 ⟶ 354.55. The linear calibration curve of the concentration range was 2-2000 ng/ml for lusutrombopag, with a lower limit of quantification (LLOQ) of 2 ng/ml. RSD of interday and intraday precision were both no more than 9.66% with the accuracy ranging from 105.82% to 108.27%. The extraction recovery of lusutrombopag was between 82.15% and 90.34%. The developed and validated method was perfectly used in the pharmacokinetic study of lusutrombopag after oral administration in rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/7290470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277053PMC
May 2020

Inhibitory Effect of Root on the Cytochrome P450 3A Enzyme in vitro and in vivo.

Drug Des Devel Ther 2020 19;14:1909-1919. Epub 2020 May 19.

Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China.

Purpose: The aim of the present study was to investigate the interactions of the main components of 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 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 T, AUC and C of midazolam in group B and group C were significantly increased (<0.05), accompanied by a significant decrease in V and CL (<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 root and midazolam synchronously.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/DDDT.S249308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250706PMC
March 2021

Hyperthermia-Triggered On-Demand Biomimetic Nanocarriers for Synergetic Photothermal and Chemotherapy.

Adv Sci (Weinh) 2020 Jun 20;7(11):1903642. Epub 2020 Apr 20.

School of Pharmaceutical Science Guangdong Provincial Key Laboratory of New Drug Screening Southern Medical University Guangzhou 510515 China.

Nanoparticle-based drug delivery systems with low side effects and enhanced efficacy hold great potential in the treatment of various malignancies, in particular cancer; however, they are still challenging to attain. Herein, an anticancer drug delivery system based on a cisplatin (CDDP) containing nanogel, functionalized with photothermal gold nanorods (GNRs) which are electrostatically decorated with doxorubicin (DOX) is reported. The nanoparticles are formed via the crosslinking reaction of hyaluronic acid with the ancillary anticarcinogen CDDP in the presence of DOX-decorated GNRs. The nanogel is furthermore cloaked with a cancer cell membrane, and the resulting biomimetic nanocarrier (4T1-HANG-GNR-DC) shows efficient accumulation by homologous tumor targeting and possesses long-time retention in the tumor microenvironment. Upon near-infrared (NIR) laser irradiation, in situ photothermal therapy is conducted which further induces hyperthermia-triggered on-demand drug release from the nanogel reservoir to achieve a synergistic photothermal/chemo-therapy. The as-developed biomimetic nanocarriers, with their dual-drug delivery features, homotypic tumor targeting and synergetic photothermal/chemo-therapy, show much promise as a potential platform for cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.201903642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284223PMC
June 2020

Effects of naringenin on the pharmacokinetics of tofacitinib in rats.

Pharm Biol 2020 Dec;58(1):225-230

Department of Orthopaedics, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, China.

Naringenin and tofacitinib are often used together for treatment of rheumatoid arthritis in Chinese clinics. This experiment investigates the effect of naringenin on the pharmacokinetics of tofacitinib in rats. Twelve Sprague-Dawley rats were randomly divided into two groups (experimental group and control group). The experimental group was pre-treated with naringenin (150 mg/kg/day) for two weeks before dosing tofacitinib, and equal amounts of CMC-Na solution in the control group. After a single oral administration of 5 mg/kg of tofacitinib, 50 μL blood samples were directly collected into 1.5 mL heparinized tubes via the caudal vein at 0.083, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. The plasma concentration of tofacitinib was quantified by UPLC/MS-MS. Results indicated that naringenin could significantly affect the pharmacokinetics of tofacitinib. The AUC of tofacitinib was increased from 1222.81 ± 222.07 to 2016.27 ± 481.62 ng/mL/h, and the difference was significant ( < 0.05). Compared with the control group, the was increased from 0.75 ± 0.29 to 3.00 ± 0.00 h ( < 0.05), and the MRT was increased from 4.90 ± 0.51 to 6.57 ± 0.66 h ( < 0.05), but the clearance was obviously decreased from 4.10 ± 0.72 to 2.42 ± 0.70 L/h/kg ( < 0.05) in experimental group. Although the and of tofacitinib were increased, there were no significant differences ( > 0.05). This research demonstrated a drug-drug interaction between naringenin and tofacitinib possibly when preadministered with naringenin; thus, we should pay attention to this possibility in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13880209.2020.1738504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144329PMC
December 2020

Micro-/Nanomotors toward Biomedical Applications: The Recent Progress in Biocompatibility.

Small 2020 07 4;16(27):e1906184. Epub 2020 Mar 4.

School of Materials Science and Engineering, Sun Yat-Sen University, Guangzhou, 510275, China.

Inspired by the highly versatile natural motors, artificial micro-/nanomotors that can convert surrounding energies into mechanical motion and accomplish multiple tasks are devised. In the past few years, micro-/nanomotors have demonstrated significant potential in biomedicine. However, the practical biomedical applications of these small-scale devices are still at an infant stage. For successful bench-to-bed translation, biocompatibility of micro-/nanomotor systems is the central issue to be considered. Herein, the recent progress in micro-/nanomotors in biocompatibility is reviewed, with a special focus on their biomedical applications. Through close collaboration between researches in the nanoengineering, material chemistry, and biomedical fields, it is expected that a promising real-world application platform based on micro-/nanomotors will emerge in the near future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smll.201906184DOI Listing
July 2020

Cytochrome P450-Based Drug-Drug Interactions of Vonoprazan and .

Front Pharmacol 2020 14;11:53. Epub 2020 Feb 14.

Department of Gastroenterology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.

Background: Vonoprazan fumarate is a potassium-competitive acid blocker that was developed as a novel acid-suppressing drug for multiple indications. As a potential alternative to proton-pump inhibitors, the determination of the drug-drug interactions is vital for further applications. Probe drug cocktails are a type of rapid, economical, and efficient approach for evaluating cytochrome P450 enzyme activities. Since vonoprazan is metabolized partly by cytochrome P450, cocktails were used to study CYP-based drug-drug interactions.

Methods: This study was conducted both and . In the study of rat liver microsomes, ultra-performance liquid chromatography coupled to tandem mass spectrometry was utilized to assess the reversible inhibition of cytochrome P450 by vonoprazan by determining the concentration of probe drugs (phenacetin, bupropion, tolbutamide, dextromethorphan, midazolam, chlorzoxazone). The differences in the levels of probe drugs between the rat groups with or without vonoprazan administration were also tested in the rats.

Results: analysis revealed that the IC values of midazolam, tolbutamide, dextromethorphan, and bupropion in rat microsomes were 22.48, 18.34, 3.62, and 3.68 μM, respectively, while chlorzoxazone and phenacetin displayed no inhibition. analysis revealed that midazolam, bupropion, dextromethorphan, and tolbutamide showed significant ( < 0.05) differences in distinct pharmacokinetic parameters after vonoprazan administration, while those of chlorzoxazone and phenacetin were not significantly different.

Conclusion: The and results indicated that vonoprazan can inhibit CYP3A4, CYP2C9, CYP2D6, and CYP2B6, suggesting that the coadministration of vonoprazan with cytochrome P450 substrates should be performed cautiously in clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033572PMC
February 2020

Effects of 26 Recombinant CYP3A4 Variants on Brexpiprazole Metabolism.

Chem Res Toxicol 2020 01 17;33(1):172-180. Epub 2019 Oct 17.

School of Pharmaceutical Sciences , Wenzhou Medical University , Wenzhou , Zhejiang 325035 , China.

As a new atypical antipsychotic, brexpiprazole is primarily metabolized by cytochrome P450 3A4 (CYP3A4). However, genetic polymorphisms in CYP3A4 cause wide variability in individuals' responses to brexpiprazole, leading to unpredictable adverse side effects or even therapeutic failure. The present study was designed to systematically study the effects of 26 recombinant CYP3A4 variants on the metabolism of brexpiprazole and investigate their enzymatic activity. Wild-type CYP3A4 and the 26 variants were incubated with the substrate brexpiprazole for 30 min at 37 °C. The metabolite DM-3411 was detected using ultraperformance liquid chromatography-tandem mass spectrometry. The activity of the wild-type CYP3A4 and 26 of its variants was analyzed. Then, the mechanism underlying the changes in enzyme function was observed using molecular dynamics simulations and molecular docking. Compared with CYP3A4.1, the enzymatic activities of CYP3A4.19, -.24, and -.28 were not significantly different (from 91.82% to 96.25%), but CYP3A4.14 and CYP3A4.15 exhibited higher enzyme activity (from 117.9 to 127.5%). The remaining 21 isoforms, including CYP3A4.2, -.3, -.4, -.5, -.7, -.8, -.9, -.10, -.11, -.12, -.13, -.16, -.17, -.18, -.20, -.23, -.29, -.31, -.32, -.33 and -.34, displayed lower enzymatic activities (from 2.90% to 75.72%). The results obtained from computer modeling indicated that weak binding affinity impaired the function of CYP3A4.32. Mutations that occur around the active site might lead to a loss of enzymatic activity, while the variants located far away from the active site perhaps had little effect on function of CYP3A4. These comprehensive data provide a reference and prediction for treatment strategies and risk assessments of brexpiprazole.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.chemrestox.9b00186DOI Listing
January 2020

Pharmacokinetic Study of Delavinone in Mice after Intravenous and Oral Administration by UPLC-MS/MS.

Biomed Res Int 2019 21;2019:3163218. Epub 2019 Mar 21.

Analytical and Testing Centre, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.

Thirty-one compounds, including delavinone, were isolated from the methanol extract of by modern chromatographic techniques. The pharmacological action of is widely used in clinical practice. However, the pharmacokinetic studies on delavinone have not been reported. Therefore, the chemical constituents of this species were investigated. Therefore, it is necessary to establish an analytical method to monitor the concentration of delavinone. An UPLC-MS/MS method was established to determine delavinone in the mouse blood, and the pharmacokinetics of delavinone after intravenous (1.0 mg/kg) and intragastric (2.5, 10.0 mg/kg) administration were studied. The lower limit of quantification was 1.0 ng/mL. The intraday and interday precision RSD were less than 13%, the accuracy ranged from 96.8% to 104.9%, the average recovery was better than 80.6%, and the matrix effect was between 88.8% and 103.4%. The UPLC-MS/MS method has been successfully applied to the pharmacokinetics of delavinone in mice. The noncompartment model was used to fit the main pharmacokinetic parameters. It was found that AUC in mice was higher than that in mice given orally, and the bioavailability of delavinone was 12.4%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/3163218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448330PMC
August 2019

The Application of Micro- and Nanomotors in Classified Drug Delivery.

Chem Asian J 2019 Jul 2;14(14):2336-2347. Epub 2019 May 2.

School of Pharmaceutical Science, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China.

Micro and nanomotors (MNMs) are micro/nanoscale devices that are able to convert chemical or external energy into mechanical motion. Based on a multitude of propulsion mechanisms, synthetic MNMs have been developed over the past decades for diverse biomedical applications, particularly drug delivery. Herein, we set out the classification of drugs delivered by MNMs, such as small molecules, nucleic acid, peptides, antibodies, and other proteins, and discuss their current limitations and possibilities in in vivo applications. Challenges and future perspectives are also discussed. With the increasing research enthusiasm in this field and the strengthening of multidisciplinary cooperation, intelligent MNMs will appear in the near future, which will have a profound impact on all related fields.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/asia.201900274DOI Listing
July 2019

Determination and pharmacokinetic study of AZD-3759 in rat plasma by ultra performance liquid chromatography with triple quadrupole mass spectrometer.

Thorac Cancer 2018 11 5;9(11):1383-1389. Epub 2018 Sep 5.

Department of Neurology, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, China.

Background: AZD-3759 is a new, potent, oral, active central nervous system-penetrant EGFR inhibitor. Despite promising clinical activity among patients pretreated and never treated with EGFR-tyrosine kinase inhibitors, no time saving pharmacokinetic study method has been reported in an animal model.

Methods: Protein was precipitated with acetonitrile and then used for sample pre-processing. A CORTECS BEH C18 column was used to separate the analytes at 40°C. Acetonitrile and water (containing 0.1% formic acid) were chosen as the mobile phase at a flow rate of 0.4 mL/min. The analytes were quantified by multiple reaction monitoring mode with positive electrospray ionization.

Results: The target fragment ions were m/z 460.38→141 for AZD-3759 and m/z 285.1→193.1 for internal standard diazepam. The calibration curve exhibited good linearity for AZD-3759 at a range of 1-500 ng/mL. The intra-run and inter-run precision variations were both < 8.22%. The recovery rate of AZD-3759 from plasma was > 76.4%.

Conclusion: An accurate, simple ultra performance liquid chromatography with triple quadrupole mass spectrometer method was developed and validated to determine AZD-3759 in rat plasma. Our validated method can be applied to the pharmacokinetic study of AZD-3759 at an oral dosage of 10 mg/kg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1759-7714.12843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209780PMC
November 2018

Indomethacin-based stimuli-responsive micelles combined with paclitaxel to overcome multidrug resistance.

Oncotarget 2017 Dec 30;8(67):111281-111294. Epub 2017 Nov 30.

Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.

Development of multidrug resistance against antitumor agents is a major limiting factor for the successful chemotherapy. Currently, both amphiphilic polymeric micelles and chemosensitizers have been proposed to overcome MDR during chemotherapy. Herein, the redox-responsive polymeric micelles composed of dextran and indomethacin (as chemosensitizer) using a disulfide bond as the linker are prepared (DEX-SS-IND) for delivery of antitumor agent paclitaxel (PTX). The high level of glutathione in tumor cells selectively breaks the disulfide bond, leading to the rapid breakdown and deformation of redox-responsive polymeric micelles. The data show that DEX-SS-IND can spontaneously form the stable micelles with high loading content (9.48 ± 0.41%), a favorable size of 45 nm with a narrow polydispersity (0.157), good stability, and glutathione-triggered drug release behavior due to the rapid breakdown of disulfide bond between DEX and IND. antitumor assay shows DEX-SS-IND/PTX micelles effectively inhibit the proliferation of PTX-resistant breast cancer (MCF-7/PTX) cells. More impressively, DEX-SS-IND/PTX micelles possess the improved plasma pharmacokinetics, enhanced antitumor efficacy on tumor growth in the xenograft models of MCF-7/PTX cells, and better safety. Overall, DEX-SS-IND/PTX micelles display a great potential for cancer treatment, especially for multidrug resistance tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.22781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762321PMC
December 2017

Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer.

Int J Nanomedicine 2017 22;12:6153-6168. Epub 2017 Aug 22.

Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Multidrug resistance (MDR) against chemotherapeutic agents has become one of the major obstacles to successful cancer therapy and MDR-associated proteins (MRPs)-mediated drug efflux is the key factor for MDR. In this study, a redox-responsive polymer based on dextran (DEX) and indomethacin (IND), which could reduce MRPs-mediated efflux of chemotherapeutics, was synthesized, and the obtained polymer could spontaneously form stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 50 nm and effectively encapsulate doxorubicin (DOX); the micelles contain a disulfide bridge (cystamine, SS) between IND and DEX (DEX-SS-IND). In vitro drug release results indicated that DEX-SS-IND/DOX micelles could maintain good stability in a stimulated normal physiological environment and promptly depolymerized and released DOX in a reducing environment. After incubating DEX-SS-IND/DOX micelles with drug-resistant tumor (MCF-7/ADR) cells, the intracellular accumulation and retention of DOX were significantly increased under the synergistic effects of redox-responsive delivery and the inhibitory effect of IND on MRPs. In vitro cytotoxicity showed that DEX-SS-IND/DOX micelles exhibited higher cytotoxicity against MCF-7/ADR cells. Moreover, DEX-SS-IND/DOX micelles showed significantly enhanced inhibition of tumor in BALB/c nude mice bearing MCF-7/ADR tumors and reduced systemic toxicity. Overall, the cumulative evidence indicates that DEX-SS-IND/DOX micelles hold significant promise for overcoming MDR for cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S141229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574666PMC
December 2017

Effect of codeine on CYP450 isoform activity of rats.

Pharm Biol 2017 Dec;55(1):1223-1227

d The Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University , Wenzhou , China.

Context: Codeine, also known as 3-methylmorphine, is an opiate used to treat pain, as a cough medicine and for diarrhoea. No study on the effects of codeine on the metabolic capacity of CYP enzyme is reported.

Objective: In order to investigate the effects of codeine on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of CYP2B1, CYP2D1, CYP1A2, CYP3A2 and CYP2C11.

Materials And Methods: Sprague-Dawley rats were randomly divided into codeine group (low, medium, high) and control group. The codeine group rats were given 4, 8, 16 mg/kg (low, medium, high) codeine by continuous intragastric administration for 14 days. Five probe drugs bupropion, metroprolol, phenacetin, midazolam and tolbutamide were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS.

Results And Conclusion: The pharmacokinetic parameters of bupropion and metroprolol experienced obvious change with AUC, C increased and CL decreased for bupropion in medium dosage group and midazolam low dosage group. This result indicates that the 14 day-intragastric administration of codeine may inhibit the metabolism of bupropion (CYP2B1) and midazolam (CYP3A2) in rat. Additional, there are no statistical differences for albumin (ALB), alkaline phosphatase (ALP), creatinine (Cr) after 14 intragastric administration of codeine, while alanine aminotransferase (ALT), aspartate aminotransferase (AST), uric acid (UA) increased compared to control group. The biomedical test results show continuous 14 day-intragastric administration of codeine would cause liver damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13880209.2017.1297466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130733PMC
December 2017

Pharmacokinetic study of ardisiacrispin A in rat plasma after intravenous administration by UPLC-MS/MS.

Biomed Chromatogr 2017 Mar 16;31(3). Epub 2016 Sep 16.

The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.

In this work, a sensitive and selective UPLC-MS/MS method for determination of ardisiacrispin A in rat plasma was developed. Cyasterone used as an internal standard (IS) and protein precipitation by acetonitrile-methanol (9:1, v/v) was used to prepare samples. Chromatographic separation was achieved on a UPLC BEH C column (2.1 × 100 mm, 1.7 μm) with 0.1% formic acid and acetonitrile as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reaction monitoring mode was used for quantification using target fragment ions m/z 1083.5 → 407.1 for ardisiacrispin A and m/z 521.3 → 485.2 for IS. Calibration plots were linear throughout the range 5-2000 ng/mL for ardisiacrispin A in rat plasma. Mean recoveries of ardisiacrispin A in rat plasma ranged from 80.4 to 92.6%. The values of RSD of intra- and inter-day precision were both <11%. The accuracy of the method was between 97.3 and 105.6%. The method was successfully applied to pharmacokinetic study of ardisiacrispin A after intravenous administration in rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bmc.3826DOI Listing
March 2017