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Advances in Pharmacokinetics and Bioanalysis of Novel Drugs
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Advances in Pharmacokinetics and Bioanalysis of Novel Drugs

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Analytical Chemistry".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 11897

Special Issue Editors

Prof. Dr. Caisheng Wu

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Guest Editor
Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cell Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
Interests: bioanalysis; pharmacokinetics; ADME; HPLC-HRMS; intelligent MS dataset mining technique
Special Issues, Collections and Topics in MDPI journals
Dr. Yingfei Li

E-Mail Website
Guest Editor
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
Interests: bioanalysis; pharmacokinetics; herb–drug interaction; TCM; PK-PD modeling
Dr. Xiaoqiang Xiang

E-Mail Website
Guest Editor
Department of Clinical Pharmacy , School of Pharmacy, Fudan University, Shanghai , China
Interests: physiologically-based pharmacokinetic modeling; drug–drug interactions; pharmacogenomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In terms of treating complex diseases, such as malignant tumors, sudden infectious diseases, cardio-cerebrovascular diseases, and diabetes, the limitations of clinical treatment with single small-molecular chemical drug are obvious. In this case, a number of combination therapies (i.e., nanodrug formulation or macromolecular drugs) have attracted increasing interests. Furthermore, traditional medicines (i.e., traditional Chinese medicine (TCM)) are also bursting with elevated vitality for continuous innovation. However, nanodrugs, macromolecular drugs, and TCM have a shared characteristic, which is their complex and diverse compositions. As a result, they are facing difficulty in drug metabolism exploration and bioanalysis in vivo. With the continuous development of novel analytical technology, innovative materials, and AI technology, multiple novel bioanalytical methods and PK/PD prediction models for metabolic research on novel drugs in complex systems have emerged.

On this basis, we are planning this Special Issue of Molecules, titled “Advances in Pharmacokinetics and Bioanalysis of Novel Drugs”, that brings together research and review articles. The papers could be focused on, but not limited to, ADME characterization of novel drugs, screen reasonable PK/TK markers, multicomponent pharmacokinetic modeling, and novel methods and techniques for bioanalysis. We hope this issue will promote in-depth understanding on the pharmacokinetics and bioanalytical methods for novel drugs.

Dr. Caisheng Wu
Dr. Yingfei Li
Dr. Xiaoqiang Xiang
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • novel drugs
  • nanodrug formulation
  • macromolecular drugs
  • traditional Chinese medicine
  • bioanalytical methods
  • PK/PD prediction models
  • ADME characterization

Published Papers (8 papers)

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Research

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14 pages, 3473 KiB  
Article
Simultaneous Determination of Five Iridoids of Picrorhiza scrophulariiflora in Rat Plasma Using UHPLC-ESI-MS/MS
by Zhibin Wang, Xuepeng Shi, Shuang Jiang, Jiahui Sun, Gilwa Borjigin, Qi Li, Yuanqiu Mu, Chunjuan Yang, Zhenyue Wang and Haixue Kuang
Molecules 2023, 28(15), 5925; https://doi.org/10.3390/molecules28155925 - 07 Aug 2023
Viewed by 772
Abstract
In this study, we developed an ultra-performance liquid chromatography-electrospray tandem quadrupole mass spectrometry (UHPLC-ESI-MS/MS) method to simultaneously determine Picroside-I, Picroside-II, Picroside-III, minecoside, and sweroside in rat plasma. The chromatographic column was an ACQUITY UHPLC® BEH Amide Column (2.1 × 100 mm, 1.7 [...] Read more.
In this study, we developed an ultra-performance liquid chromatography-electrospray tandem quadrupole mass spectrometry (UHPLC-ESI-MS/MS) method to simultaneously determine Picroside-I, Picroside-II, Picroside-III, minecoside, and sweroside in rat plasma. The chromatographic column was an ACQUITY UHPLC® BEH Amide Column (2.1 × 100 mm, 1.7 µm; Waters, MA, USA), column temperature 40 °C. The mobile phase was 0.1% formic acid aqueous solution–0.1% formic acid acetonitrile solution. The flow rate was 0.4 mL/min. Multiple reaction monitoring (MRM) and negative ion modes were adopted. The results showed that the calibration curves of five compounds in plasma showed good linearity (r > 0.9911) over the studied dose range. The lower limits of quantification (LLOQ) for Picroside-I, Picroside-II, Picroside-III, minecoside, and sweroside were 6.876, 5.193, 5.040, 1.260, and 4.527 ng/mL, respectively. The intra-day and inter-day precision were <15%. The matrix effects ranged from 95.77 to 101.9%. The Tmax were 1.1 ± 0.2, 1.1 ± 0.1, 0.8 ± 0.1, 1.0 ± 0.2, and 2.1 ± 0.1 h. This study will be useful in understanding the behavior of drugs in the body and the body’s effect on drugs. It also offers theoretical underpinnings and highlights the importance of clinical applications and creating novel drugs. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics and Bioanalysis of Novel Drugs)
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15 pages, 2853 KiB  
Article
Generic Methods for Simultaneous Analysis of Four Direct Oral Anticoagulants in Human Plasma and Urine by Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry
by Jian-Wei Ren, Xin Zheng and Xiao-Hong Han
Molecules 2023, 28(5), 2254; https://doi.org/10.3390/molecules28052254 - 28 Feb 2023
Cited by 2 | Viewed by 1389
Abstract
The new direct oral anticoagulants (DOACs) are increasingly used to treat and prevent thromboembolic disorders, and monitoring concentrations may be valuable in some special scenarios to prevent clinical adverse events. This study aimed to develop generic methods for the rapid and simultaneous analysis [...] Read more.
The new direct oral anticoagulants (DOACs) are increasingly used to treat and prevent thromboembolic disorders, and monitoring concentrations may be valuable in some special scenarios to prevent clinical adverse events. This study aimed to develop generic methods for the rapid and simultaneous analysis of four DOACs in human plasma and urine. Protein precipitation and one-step dilution were used to prepare the plasma and urine; the extracts were injected to ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for analysis. Chromatographic separation was performed on an Acquity™ UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm) with gradient elution of 7 min. A triple quadrupole tandem mass spectrometer with an electrospray ionization source was employed to analyze DOACs in a positive ion mode. The methods showed great linearity in the plasma (1~500 ng/mL) and urine (10~10,000 ng/mL) for all analytes (R2 ≥ 0.99). The intra- and inter-day precision and accuracy were within acceptance criteria. The matrix effect and extraction recovery were 86.5~97.5% and 93.5~104.7% in the plasma, while 97.0~101.9% and 85.1~99.5% in the urine. The stability of samples during the routine preparation and storage were within the acceptance criteria of less than ±15%. The methods developed were accurate, reliable, and simple for the rapid and simultaneous measurement of four DOACs in human plasma and urine, and successfully applied to patients and subjects with DOACs therapy for anticoagulant activity assessment. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics and Bioanalysis of Novel Drugs)
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16 pages, 2227 KiB  
Article
Pharmacokinetics of Novel Furoxan/Coumarin Hybrids in Rats Using LC-MS/MS Method and Physiologically Based Pharmacokinetic Model
by Yawen Yuan, Zhihong Li, Ke Wang, Shunguo Zhang, Qingfeng He, Lucy Liu, Zhijia Tang, Xiao Zhu, Ying Chen, Weimin Cai, Chao Peng and Xiaoqiang Xiang
Molecules 2023, 28(2), 837; https://doi.org/10.3390/molecules28020837 - 13 Jan 2023
Viewed by 1437
Abstract
Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, [...] Read more.
Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01–1.0 μg/mL. The free drug fraction (fu) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics and Bioanalysis of Novel Drugs)
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12 pages, 2648 KiB  
Article
Analysis of Intestinal Metabolites in SR−B1 Knockout Mice via Ultra−Performance Liquid Chromatography Quadrupole Time−of−Flight Mass Spectrometry
by Qijun Chen, Lixue Wang, Jinlong Chen, Hui Song, Wen Xing, Ziqian Wang, Xueying Song, Hua Yang and Wenhua Zhao
Molecules 2023, 28(2), 610; https://doi.org/10.3390/molecules28020610 - 06 Jan 2023
Cited by 1 | Viewed by 1073
Abstract
Scavenger receptor class B type 1 (SR−B1), a multiligand membrane receptor, is expressed in a gradient along the gastrocolic axis. SR−B1 deficiency enhances lymphocyte proliferation and elevates inflammatory cytokine production in macrophages. However, whether SR−B1 affects intestinal metabolites is unclear. In this study, [...] Read more.
Scavenger receptor class B type 1 (SR−B1), a multiligand membrane receptor, is expressed in a gradient along the gastrocolic axis. SR−B1 deficiency enhances lymphocyte proliferation and elevates inflammatory cytokine production in macrophages. However, whether SR−B1 affects intestinal metabolites is unclear. In this study, we detected metabolite changes in the intestinal tissue of SR−B1−/− mice, including amino acids and neurotransmitters, by ultra−performance liquid chromatography quadrupole time−of−flight mass spectrometry (UHPLC−Q−TOF/MS) and HPLC. We found that SR−B1−/− mice exhibited changes in intestinal lipid metabolites and metabolic pathways, including the glycerophospholipid, sphingolipid, linoleic acid, taurine, and hypotaurine metabolic pathways. SR−B1 deficiency influenced the contents of amino acids and neurotransmitters in all parts of the intestine; the contents of leucine (LEU), phenylalanine (PHE), tryptophan (TRP), and tyrosine (TYR) were affected in all parts of the intestine; and the contents of 3,4−dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) were significantly decreased in both the colon and rectum. In summary, SR−B1 deficiency regulated intestinal lipids, amino acids, and neurotransmitter metabolism in mice. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics and Bioanalysis of Novel Drugs)
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18 pages, 2659 KiB  
Article
A Network-Pharmacology-Combined Integrated Pharmacokinetic Strategy to Investigate the Mechanism of Potential Liver Injury due to Polygonum multiflorum
by Zhixin Jia, Lirong Liu, Cong Fang, Mingxia Pan, Shiyu Cong, Zhonghui Guo, Xiaoqin Yang, Jie Liu, Yueting Li and Hongbin Xiao
Molecules 2022, 27(23), 8592; https://doi.org/10.3390/molecules27238592 - 06 Dec 2022
Viewed by 1222
Abstract
Polygonum multiflorum (PM) has been used as a tonic and anti-aging remedy for centuries in Asian countries. However, its application in the clinic has been hindered by its potential to cause liver injury and the lack of investigations into this mechanism. Here, we [...] Read more.
Polygonum multiflorum (PM) has been used as a tonic and anti-aging remedy for centuries in Asian countries. However, its application in the clinic has been hindered by its potential to cause liver injury and the lack of investigations into this mechanism. Here, we established a strategy using a network pharmacological technique combined with integrated pharmacokinetics to provide an applicable approach for addressing this issue. A fast and sensitive HPLC-QQQ-MS method was developed for the simultaneous quantification of five effective compounds (trans-2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside, emodin-8-O-β-d-glucoside, physcion-8-O-β-d-glucoside, aloe-emodin and emodin). The method was fully validated in terms of specificity, linearity, accuracy, precision, extraction recovery, matrix effects, and stability. The lower limits of quantification were 0.125–0.500 ng/mL. This well-validated method was successfully applied to an integrated pharmacokinetic study of PM extract in rats. The network pharmacological technique was used to evaluate the potential liver injury due to the five absorbed components. Through pathway enrichment analysis, it was found that potential liver injury is primarily associated with PI3K-Akt, MAPK, Rap1, and Ras signaling pathways. In brief, the combined strategy might be valuable in revealing the mechanism of potential liver injury due to PM. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics and Bioanalysis of Novel Drugs)
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13 pages, 3722 KiB  
Article
Stepwise Diagnostic Product Ions Filtering Strategy for Rapid Discovery of Diterpenoids in Scutellaria barbata Based on UHPLC-Q-Exactive-Orbitrap-MS
by Xinhua Zhou, Xu Chen, Liping Fan, Huirong Dong, Yan Ren and Xiangming Chen
Molecules 2022, 27(23), 8185; https://doi.org/10.3390/molecules27238185 - 24 Nov 2022
Cited by 3 | Viewed by 1069
Abstract
Diterpenoids are considered the major bioactive components in Scutellaria barbata to treat cancer and inflammation, but few comprehensive profiling studies of diterpenoids have been reported. Herein, a stepwise diagnostic product ions (DPIs) filtering strategy for efficient and targeted profiling of diterpenoids in Scutellaria [...] Read more.
Diterpenoids are considered the major bioactive components in Scutellaria barbata to treat cancer and inflammation, but few comprehensive profiling studies of diterpenoids have been reported. Herein, a stepwise diagnostic product ions (DPIs) filtering strategy for efficient and targeted profiling of diterpenoids in Scutellaria barbata was developed using UHPLC-Q-Exactive-Orbitrap-MS. After UHPLC-HRMS/MS analysis of six diterpenoid reference standards, fragmentation behaviors of these references were studied to provide DPIs. Then, stepwise DPIs filtering aimed to reduce the potential interferences of matrix ions and achieve more chromatographic peaks was conducted to rapidly screen the diterpenoids. The results demonstrated that stepwise DPIs were capable of simplifying the workload in data post-processing and the effective acquisition of low abundance compounds. Subsequently, DPIs and MS/MS fragment patterns were adopted to identify the targeted diterpenoids. As a result, 381 diterpenoids were unambiguously or tentatively identified, while 141 of them with completely new molecular weights were potential new diterpenoids for Scutellaria barbata. These results demonstrate that the developed stepwise DPIs filtering method could be employed as an efficient, reliable, and valuable strategy to screen and identify the diterpenoid profile in Scutellaria barbata. This might accelerate and simplify target constituent profiling from traditional Chinese medicine (TCM) extracts. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics and Bioanalysis of Novel Drugs)
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16 pages, 2477 KiB  
Article
High-Throughput Metabolic Soft-Spot Identification in Liver Microsomes by LC/UV/MS: Application of a Single Variable Incubation Time Approach
by Yanlin Zhu, Guiying Chen, Kerong Zhang, Chang Chen, Weiqing Chen, Mingshe Zhu and Hongliang Jiang
Molecules 2022, 27(22), 8058; https://doi.org/10.3390/molecules27228058 - 20 Nov 2022
Cited by 1 | Viewed by 1820
Abstract
CYP-mediated fast metabolism may lead to poor bioavailability, fast drug clearance and significant drug interaction. Thus, metabolic stability screening in human liver microsomes (HLM) followed by metabolic soft-spot identification (MSSID) is routinely conducted in drug discovery. Liver microsomal incubations of testing compounds with [...] Read more.
CYP-mediated fast metabolism may lead to poor bioavailability, fast drug clearance and significant drug interaction. Thus, metabolic stability screening in human liver microsomes (HLM) followed by metabolic soft-spot identification (MSSID) is routinely conducted in drug discovery. Liver microsomal incubations of testing compounds with fixed single or multiple incubation time(s) and quantitative and qualitative analysis of metabolites using high-resolution mass spectrometry are routinely employed in MSSID assays. The major objective of this study was to develop and validate a simple, effective, and high-throughput assay for determining metabolic soft-spots of testing compounds in liver microsomes using a single variable incubation time and LC/UV/MS. Model compounds (verapamil, dextromethorphan, buspirone, mirtazapine, saquinavir, midazolam, amodiaquine) were incubated at 3 or 5 µM with HLM for a single variable incubation time between 1 and 60 min based on predetermined metabolic stability data. As a result, disappearances of the parents were around 20–40%, and only one or a few primary metabolites were generated as major metabolite(s) without notable formation of secondary metabolites. The unique metabolite profiles generated from the optimal incubation conditions enabled LC/UV to perform direct quantitative estimation for identifying major metabolites. Consequently, structural characterization by LC/MS focused on one or a few major primary metabolite(s) rather than many metabolites including secondary metabolites. Furthermore, generic data-dependent acquisition methods were utilized to enable Q-TOF and Qtrap to continuously record full MS and MS/MS spectral data of major metabolites for post-acquisition data-mining and interpretation. Results from analyzing metabolic soft-spots of the seven model compounds demonstrated that the novel MSSID assay can substantially simplify metabolic soft-spot identification and is well suited for high-throughput analysis in lead optimization. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics and Bioanalysis of Novel Drugs)
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Review

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16 pages, 654 KiB  
Review
Utilization of Physiologically Based Pharmacokinetic Modeling in Pharmacokinetic Study of Natural Medicine: An Overview
by Qiuyu Jia, Qingfeng He, Li Yao, Min Li, Jiaying Lin, Zhijia Tang, Xiao Zhu and Xiaoqiang Xiang
Molecules 2022, 27(24), 8670; https://doi.org/10.3390/molecules27248670 - 08 Dec 2022
Cited by 2 | Viewed by 2197
Abstract
Natural medicine has been widely used for clinical treatment and health care in many countries and regions. Additionally, extracting active ingredients from traditional Chinese medicine and other natural plants, defining their chemical structure and pharmacological effects, and screening potential druggable candidates are also [...] Read more.
Natural medicine has been widely used for clinical treatment and health care in many countries and regions. Additionally, extracting active ingredients from traditional Chinese medicine and other natural plants, defining their chemical structure and pharmacological effects, and screening potential druggable candidates are also uprising directions in new drug research and development. Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique that simulates the absorption, distribution, metabolism, and elimination of drugs in various tissues and organs in vivo based on physiological and anatomical characteristics and physicochemical properties. PBPK modeling in drug research and development has gradually been recognized by regulatory authorities in recent years, including the U.S. Food and Drug Administration. This review summarizes the general situation and shortcomings of the current research on the pharmacokinetics of natural medicine and introduces the concept and the advantages of the PBPK model in the study of pharmacokinetics of natural medicine. Finally, the pharmacokinetic studies of natural medicine using the PBPK models are summed up, followed by discussions on the applications of PBPK modeling to the enzyme-mediated pharmacokinetic changes, special populations, new drug research and development, and new indication adding for natural medicine. This paper aims to provide a novel strategy for the preclinical research and clinical use of natural medicine. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics and Bioanalysis of Novel Drugs)
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