Chunnuan Wu

Tianjin Medical University Cancer Institute and Hospital

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Jin Sun

Shenyang Pharmaceutical University

Zhonggui He

Shenyang Pharmaceutical University

Zhonggui He

Shenyang Pharmaceutical University

Xiaoyu Ai

Nankai University

Cong Luo

Shenyang Pharmaceutical University

Yongjun Wang

Shenyang Pharmaceutical University

He Lian

Shenyang Pharmaceutical University

Yinghua Sun

Shenyang Pharmaceutical University

Yuqian Du

ZheJiang Academy of Agricultural Sciences

Xiaopeng Han

Shenyang Center for Disease Control and Prevention

Cooperative Institutions

Shenyang Pharmaceutical University

Tianjin Medical University Cancer Institute and Hospital

Chinese Academy of Sciences

Chinese Academy of Medical Sciences & Peking Union Medical College

Peking University

Sichuan University

Capital Medical University

Central South University

Ministry of Education of the People's Republic of China

Beijing University of Chinese Medicine

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Determination of Doxorubicin in Stealth Hyalurionic Acid-Based Nanoparticles in Rat Plasma by the Liquid–Liquid Nanoparticles-Breaking Extraction Method: Application to a Pharmacokinetic Study

Journal of Chromatographic Science (2016)

Xiaopeng Han Wei Wei Lu Zhong Cong Luo Chunnuan Wu

An efficient extraction of doxorubicin (Dox) from homemade stealth hyalurionic acid (HA)-based nanoparticles (NPs) in rat plasma could not be performed by previously published methods. Therefore, we attempted to establish the novel NPs-breaking and UPLC-MS-MS method for evaluating the pharmacokinetic profiles of the homemade stealth HA NPs in rats. The pretreatment method of plasma samples used the liquid-liquid extraction method with isopropyl alcohol as NPs-breaking and protein-precipitating solvents, and the NPs-breaking efficiency of isopropyl alcohol was as high as 97.2%. The analyte and gliclazide (internal standard) were extracted from plasma samples with isopropyl alcohol and were separated on UPLC BEH C18 with a mobile phase consisting of methanol and water (containing 0.1% formic acid). The method demonstrated good linearity at the concentrations ranging from 5 to 5,000 ng/mL. The intra- and interday relative standard deviations were >10%. Finally, the method was successfully applied to a pharmacokinetic study of homemade stealth HA-based NPs in rats following intravenous administration.

Isopropyl alcohol

Liquid–liquid extraction

Isopropyl myristate

10.1093/chromsci/bmw074

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Citations (4)

Prediction for optimal dosage of pazopanib under various clinical situations using physiologically based pharmacokinetic modeling

Frontiers in Pharmacology (2022)

Chunnuan Wu Bole Li Shuai Meng Linghui Qie Jie Zhang

This study aimed to apply a physiologically based pharmacokinetic (PBPK) model to predict optimal dosing regimens of pazopanib (PAZ) for safe and effective administration when co-administered with CYP3A4 inhibitors, acid-reducing agents, food, and administered in patients with hepatic impairment. Here, we have successfully developed the population PBPK model and the predicted PK variables by this model matched well with the clinically observed data. Most ratios of prediction to observation were between 0.5 and 2.0. Suitable dosage modifications of PAZ have been identified using the PBPK simulations in various situations, i.e., 200 mg once daily (OD) or 100 mg twice daily (BID) when co-administered with the two CYP3A4 inhibitors, 200 mg BID when simultaneously administered with food or 800 mg OD when avoiding food uptake simultaneously. Additionally, the PBPK model also suggested that dosing does not need to be adjusted when co-administered with esomeprazole and administration in patients with wild hepatic impairment. Furthermore, the PBPK model also suggested that PAZ is not recommended to be administered in patients with severe hepatic impairment. In summary, the present PBPK model can determine the optimal dosing adjustment recommendations in multiple clinical uses, which cannot be achieved by only focusing on AUC linear change of PK.

10.3389/fphar.2022.963311

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Citations (10)

Bioadhesive chitosan-coated cyclodextrin-based superamolecular nanomicelles to enhance the oral bioavailability of doxorubicin

Journal of Nanoparticle Research (2014)

Yuhai Liu Yinglei Zhai Xiaopeng Han Xiaohong Liu Wanjun Liu

10.1007/s11051-014-2587-8

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Structure‐based prediction of human intestinal membrane permeability for rapid in silico BCS classification

Biopharmaceutics & Drug Disposition (2013)

Le Sun Xiaohong Liu Rongwu Xiang Chunnuan Wu Yongjun Wang

Human effective intestinal membrane permeability (Peff) is one of the two important indicators for drug classification according to the Biopharmaceutical Classification System (BCS), and contributes greatly to the performance of oral drug absorption. Here, a structure-based in silico predictive model of Peff was developed successfully to facilitate in silico BCS classification in the early stage of drug discovery, even before the compound was synthesized. The quantitative structure-Peff relationship for 30 drugs was constructed based on seven structural parameters. Then the model was built by the multiple linear regression method and internally validated by the residual analysis, the normal probability-probability plot and the Williams plot. For the entire data set, the R² and adjusted R² values were 0.782 and 0.712, respectively. The results indicated that the fitted model was robust, stable and satisfied all the prerequisites of the regression models. As for the 102 tested drugs, the predicted Peff values had a good correlation with the experimental human absorbed fraction (Fa). This model was also used to perform high/low Peff classification for 57 drugs that have been classified according to the BCS, and 72% of drugs could be classified correctly, indicating that the developed model can be used for rapid BCS classification in the early stages of drug discovery.

Biopharmaceutical

Membrane permeability

Plot (graphics)

10.1002/bdd.1848

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Cotransporting Ion is a Trigger for Cellular Endocytosis of Transporter‐Targeting Nanoparticles: A Case Study of High‐Efficiency SLC22A5 (OCTN2)‐Mediated Carnitine‐Conjugated Nanoparticles for Oral Delivery of Therapeutic Drugs

Advanced Healthcare Materials (2017)

Longfa Kou Qing Yao Mengchi Sun Chunnuan Wu Jia Wang

OCTN2 (SLC22A5) is a Na+ -coupled absorption transporter for l-carnitine in small intestine. This study tests the potential of this transporter for oral delivery of therapeutic drugs encapsulated in l-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) and discloses the molecular mechanism for cellular endocytosis of transporter-targeting nanoparticles. Conjugation of l-carnitine to a surface of PLGA-NPs enhances the cellular uptake and intestinal absorption of encapsulated drug. In both cases, the uptake process is dependent on cotransporting ion Na+ . Computational OCTN2 docking analysis shows that the presence of Na+ is important for the formation of the energetically stable intermediate complex of transporter-Na+ -LC-PLGA NPs, which is also the first step in cellular endocytosis of nanoparticles. The transporter-mediated intestinal absorption of LC-PLGA NPs occurs via endocytosis/transcytosis rather than via the traditional transmembrane transport. The portal blood versus the lymphatic route is evaluated by the plasma appearance of the drug in the control and lymph duct-ligated rats. Absorption via the lymphatic system is the predominant route in the oral delivery of the NPs. In summary, LC-PLGA NPs can effectively target OCTN2 on the enterocytes for enhancing oral delivery of drugs and the critical role of cotransporting ions should be noticed in designing transporter-targeting nanoparticles.

10.1002/adhm.201700165

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Enhanced Oral Delivery of Paclitaxel Using Acetylcysteine Functionalized Chitosan-Vitamin E Succinate Nanomicelles Based on a Mucus Bioadhesion and Penetration Mechanism

Molecular Pharmaceutics (2013)

He Lian Tianhong Zhang Jin Sun Xiaohong Liu Guolian Ren

In addition to being a physiological protective barrier, the gastrointestinal mucosal membrane is also a primary obstacle that hinders the oral absorption of many therapeutic compounds, especially drugs with a poor permeability. In order to resolve this impasse, we have designed multifunctional nanomicelles based on the acetylcysteine functionalized chitosan-vitamin E succinate copolymer (CS-VES-NAC, CVN), which exhibit marked bioadhesion, possess the ability to penetrate mucus, and enhance the oral absorption of a hydrophobic drug with a poor penetrative profile, paclitaxel. The intestinal absorption (Ka = 0.38 ± 0.04 min(-1), Papp = 0.059 cm · min(-1)) of CVN nanomicelles was greatly improved (4.5-fold) in comparison with paclitaxel solution, and CLSM (confocal laser scanning microscope) pictures also showed not only enhanced adhesion to the intestinal surface but improved accumulation within intestinal villi. The in vivo pharmacokinetics indicated that the AUC0-t (586.37 ng/mL · h) of CVN nanomicelles was markedly enhanced compared with PTX solution. In summary, the novel multifunctional CVN nanomicelles appear to be a promising nanocarrier for insoluble and poorly permeable drugs due to their high bioadhesion and permeation-enhancing capability.

Mucoadhesion

Penetration (warfare)

10.1021/mp400282r

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Citations (75)

A rapid and sensitive LC‐MS/MS method for evaluation of the absolute oral bioavailability of a novel c‐Met tyrosine kinase inhibitor QBH‐196 in rats

Biomedical Chromatography (2015)

Qi Zhang Jin Sun Tianshu Lu Jinling Zhang Chunnuan Wu

Abstract A sensitive, selective and high‐throughput UPLC‐MS/MS method was developed and validated for the determination of a novel c‐Met tyrosine kinase inhibitor, QBH‐196, in rat plasma. QBH‐196 and its analog BH357 (IS) were extracted from rat plasma using a mixture of dichloromethane and N ‐hexane (2:3, v/v). The chromatographic separation was carried out on Phenomenex C 18 column (50 × 2.1 mm, 2.6 µm particle size) with a gradient mobile phase of methanol (A) and water containing 0.05% formic acid (B) at a flow rate of 0.2 mL/min. The assay was performed by positive electrospray ionization in multiple reaction monitoring mode using transitions of m / z 622.68 → 140.41 for QBH‐196 and m / z 591.19 →126.21 for the IS, respectively. Good linearity was obtained over the concentration range of 8.0–4000 ng/mL ( r 2 > 0.99) for QBH‐196 and the lower limit of quantification was 8.0 ng/mL in rat plasma. Validations of the method, including its sensitivity, extraction recovery, matrix effect, intra‐ and inter‐day precision, accuracy and stability, were all within acceptable limits. The established method was successfully applied to determine absolute oral bioavailability of QBH‐196 in rats for the first time. The mean oral absolute bioavailability of QBH‐196 was found to be about 40.8% and the elimination half‐life was 40.0 ± 13.1 h. This result suggested that QBH‐196 exhibits good oral absorption in vivo , which is very important for the further development of QBH‐196 as a new oral anticancer drug. Copyright © 2015 John Wiley & Sons, Ltd.

10.1002/bmc.3474

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Prediction of trough concentration and ALK occupancy in plasma and cerebrospinal fluid using physiologically based pharmacokinetic modeling of crizotinib, alectinib, and lorlatinib

Frontiers in Pharmacology (2023)

Bole Li Shan Liu Honglei Feng Chunshuang Du Liman Wei

Backgrounds: Brain metastases occur in approximately 30% of patients with non-small-cell lung cancer (NSCLC). Therefore, the free drug concentration in cerebrospinal fluid (CSF) is strongly associated with the clinical efficacy. Purpose: The present study aimed to develop physiologically based pharmacokinetic (PBPK) models that can predict the steady-state trough concentration (C trough ) in plasma and CSF, as well as anaplastic lymphoma kinase (ALK) occupancy (AO), for three inhibitors: crizotinib (CRI), alectinib (ALE), and lorlatinib (LOR). Methods: To achieve this, population PBPK models were successfully developed and validated using multiple clinical pharmacokinetics (PK) and drug–drug interaction (DDI) studies, both in healthy subjects and patients. Results: The prediction-to-observation ratios for plasma AUC, C max , and C trough in heathy subjects and patients ranged between 0.5 and 2.0. In addition, PK profiles of CRI, ALE, and LOR in CSF aligned well with observed data. Moreover, the AUC and C max ratios of the three inhibitors when co-administered with CYP3A4 inhibitors/inducers also matched with clinically observed values. Utilizing PK thresholds for effective plasma C trough and AO values on wild-type and four ALK mutations in plasma and CSF, PBPK models were then combined with the mean and 95% confidence interval to predict optimal dosing regimens. Conclusions: Overall, these PBPK models provide valuable insights into determining appropriate dosing regimens for the three ALK inhibitors, understanding their effectiveness in brain metastasis therapy, and analyzing the underlying mechanisms of on-target resistance.

Alectinib

Trough Concentration

10.3389/fphar.2023.1234262

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Citations (2)

A Mechanism of Action Study on Danggui Sini Decoction to Discover Its Therapeutic Effect on Gastric Cancer

Frontiers in Pharmacology (2021)

Boyu Pan Yun Wang Chunnuan Wu Junrong Jia Chen Huang

Danggui Sini Decoction (DSD), a classic Chinese herb medicine (CHM) formula, has been used to treat various diseases in China for centuries. However, it remains challenging to reveal its mechanism of action through conventional pharmacological methods. Here, we first explored the mechanism of action of DSD with the assistance of network pharmacology and bioinformatic analysis tools, and found a potential therapeutic effect of DSD on cancer. Indeed, our in vivo experiment demonstrated that oral administration of DSD could significantly inhibit the growth of xenografted gastric cancer (GC) on mice. The subsequent enrichment analyses for 123 candidate core targets evacuated from the drug/disease-target protein-protein interaction network showed that DSD could affect the key biological processes involving the survival and growth of GC cells, such as apoptosis and cell cycle, and the disturbance of these biological processes is likely attributed to the simultaneous inhibition of multiple signaling pathways, including PI3K/Akt, MAPK, and p53 pathways. Notably, these in silico results were further validated by a series of cellular functional and molecular biological assays in vitro . Moreover, molecular docking analysis suggested an important role of MCM2 in delivering the pharmacological activity of DSD against GC. Together, these results indicate that our network pharmacology and bioinformatics-guided approach is feasible and useful in exploring not only the mechanism of action, but also the “new use” of the old CHM formula.

Mechanism of Action

Systems pharmacology

Interaction network

10.3389/fphar.2020.592903

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Citations (19)

Development and evaluation of taste-masked dry suspension of cefuroxime axetil for enhancement of oral bioavailability

Asian Journal of Pharmaceutical Sciences (2013)

Yuqian Du Yinglei Zhai Juhong Zhang Chunnuan Wu Cong Luo

Cefuroxime axetil (CA) is an ester prodrug of cefuroxime with an unpleasant taste when administrated orally. This work was to mask the bitter taste of CA and enhance its oral bioavailability. Dry suspensions were prepared by means of wet granulation method and solid dispersion method. Binders, suspending agents and other compositions involved in the formulation were optimized. The differential scanning calorimetry (DSC) analysis indicated that CA was amorphous in the solid dispersion with stearic acid as the carrier, which contributed to an improvement of the dissolution rate. Taste evaluation was performed by three volunteers and taste masking was successfully achieved by the methods mentioned above. A pH 7.0 phosphate buffer was adopted to study the in vitro dissolution performance of the three formulations, i.e., two self-made dry suspensions and the commercial one. With a better release characteristic and a satisfying taste masking ability, the solid dispersion suspension was selected as the optimal formulation for the further pharmacokinetic study in beagle dogs. The values of Cmax and AUC0–12 for the solid dispersion suspension were about 1.78-fold and 2.17-fold higher than these of reference suspension, respectively. The obtained results demonstrated that the solid dispersion can efficiently mask the bitter taste of CA and significantly enhance its oral bioavailability.

Granulation

Suspension

10.1016/j.ajps.2013.10.001

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Citations (20)