Table of Content

Volume 26 Issue 8
26 August 2021

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Research strategies and considerations on non-clinical pharmacokinetics of nanomedicine

FU Shujun, HUANG Fanghua, GU Jingkai, WU Wei, SUN Tao, WANG Qingli

2021, 26(8):  842-850.  doi:10.12092/j.issn.1009-2501.2021.08.001

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With the rapid development of nanotechnology, the research and development of nanomedicine has become one of the current development directions of drug innovation. The pharmacokinetic characteristics of nanomedicine are significantly different from general drugs because of the scale effect based on nanostructures, and pharmacokinetics studies of nanomedicine may be different from the general drugs. This article focuses on the research strategies and considerations on non-clinical pharmacokinetics of nanomedicine, including test agents, in vivo/in vitro assays, biological sample analysis, data evaluation and analysis etc., providing references for developers.

Research progress and thinking on the metabolism of polysaccharide drugs in vivo and the key technology of PK/PD

XU Hui, YANG Xinyu, ZHAO Zhehui, WANG Yan

2021, 26(8):  851-862.  doi:10.12092/j.issn.1009-2501.2021.08.002

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Polysaccharide drugs are a type of safe and effective natural drug with a wide range of pharmacological activity such as anti-tumor, immunomodulation, and oxidation, and polysaccharide drugs are currently more concerned. However, since the molecular weight of the polysaccharide is quite large, most of which do not have ultraviolet absorption and fluorescent groups, which makes the qualitative and quantitative analysis of polysaccharides are relatively difficult. In addition, endogenous sugar substances may also cause certain interference to polysaccharide assay in biological samples, and therefore, in vivo metabolism and PK/PD key technologies in polysaccharide drugs have been research hotspots. This paper summarizes the relevant literature published in recent years, reviewing the biological activity and pharmacokinetics of polysaccharide drugs, proposing gut bacteria may be potential "organ" affecting metabolism and efficacy of polysaccharide drugs, and providing thoughts on gut bacteria mediating polysaccharide drugs in vivo and key technology research of PK/PD, in order to provide more scientific ideas for pharmacokinetics, pharmacological research and molecular mechanisms of polysaccharide drugs.

Current status of clinical drug-drug interactions research of innovative small molecule drugs in China

LIU Lu, CHEN Xiaoyan

2021, 26(8):  863-875.  doi:10.12092/j.issn.1009-2501.2021.08.003

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In order to improve the efficacy or reduce the side effects, the combination of two or more drugs is often used in clinical practice, which often brings new medication problems that change the process or efficacy of a drug in vivo due to combination. This article reviews the clinical drug-drug interaction (DDI) researches of 44 novel molecular entities which were approved to be launched in China from January 2000 to March 2021. Among them, clinical DDI trials based on test drugs as substrates of the metabolic enzymes (11/44) especially as the substrates of CYP3A4 (7/11) are dominant. The results show that most of test drugs were CYP3A4 substrates with a moderate or lower sensitivity, and no highly sensitive substrates were found. The second is the clinical DDI trials based on synergy or reducing side effects, which mainly focus on the fields of tumors, diabetes, and viral infections, and these studies have not shown pharmacokinetic interactions with clinical significance. The DDI trials of test drugs as metabolic enzyme modulators account for 7/44. And transporter-based DDI trials are relatively rare and most of them are in vitro studies. With the in-depth study of drug metabolism/transport mechanisms in vivo and in vitro, especially the development of clinical trials of radioisotope-labeled drugs and computer simulations, the overall level of DDI research in China is gradually improving, which will provide a solid scientific foundation to ensure drug safety.

Research status and prospect of transporter-mediated drug-drug interactions

MENG Qiang, LIU Kexin

2021, 26(8):  876-888.  doi:10.12092/j.issn.1009-2501.2021.08.004

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In clinic, it is very common that a variety of drugs are used in the treatment of diseases. However, the combination of drugs can easily lead to the occurrence of drug-drug interaction (DDI), which can lead to the reduction or loss of drug efficacy, the increase of adverse reactions, and even lead to serious adverse reactions. Drug transporters play an important role in the occurrence and development of DDI by influencing the disposal process of combined drugs in vivo. In this paper, the relationship between DDI and transporter was summarized. The effects of transporter-mediated DDI on the drug disposal process in vivo, and the relations of DDI and disease or multidrug resistance were reviewed. The current guiding principles of DDI research in China were briefly introduced. The purpose was to remind clinical medical workers to pay attention to transporter-mediated DDI and improve the safety of drug combination, further to provide a new vision and ideas for disease treatment and avoiding multidrug resistance.

Application of physiologically based pharmacokinetic model in drug development and several questions being thought

ZHOU Han, LIU Xiaodong

2021, 26(8):  889-913.  doi:10.12092/j.issn.1009-2501.2021.08.005

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Physiologically based pharmacokinetic (PBPK) model is based on physiology, anatomy, enzymes for drug metabolism, characteristic of drug transport, physicochemical property of drug and drug-body interaction. Thus, PBPK model may quantitatively predict: concentration-time profiles of drug and its metabolites in plasma and tissues; pharmacokinetics of drug under disease status; pharmacokinetics of drug in special population; pharmacokinetics of drugs in human derived from experimental animals; in vivo pharmacokinetics of drugs based on in vitro parameters for metabolism and transport; pharmacokinetics of drugs from different formations; pharmacodynamics or toxicity of drugs based on in vitro parameters for metabolism, transport, activity or toxicity of drug; drug-drug interaction; individual contributions of enzymes and transporters to in vivo drug disposition. Here, we would review applications of PBPK model in drug development and several questions which should be thought through a series of examples.

Construction and application of innovation gene-edited rats and intestinal 3D organoids models in drug metabolism and pharmacokinetics

ZHANG Yuanjin, HUANG Shengbo, LIU Jie, WANG Xin

2021, 26(8):  914-922.  doi:10.12092/j.issn.1009-2501.2021.08.006

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Drug metabolism and pharmacokinetics (DMPK) are the science to study the process of drug absorption, distribution, metabolism and excretion. It is very important to evaluate the characteristics of DMPK for the early development of drugs and the later clinical precision medication. The innovative construction of DMPK models promotes the development and improvement of drug evaluation system. Based on our research results, this review summarized the latest progress and application of innovative DMPK models, focusing on the following two aspects: (1) CRISPR/Cas9 gene editing rat models, including Cyp2e1-/-, Cyp3a1/2-/-, Cyp2j3/10-/-, Cyp1a2-/-, Mdr1a/1b-/-, Slco1b2-/- rats for DMPK and physiological function research. (2) 3D organoids of mouse and human small intestine, a new model to study the function of ABC (P-gp, BCRP, MRP2) transporters. These innovative animal models and organoid models not only help to evaluate the role of drug metabolic enzymes and transporters in DMPK, but also help to deeply understand their functions in normal physiological activities.

Early dectection and prediction hepatotoxic risk in vitro

LIU Wenjing, WU Zhitao, PAN Guoyu

2021, 26(8):  923-930.  doi:10.12092/j.issn.1009-2501.2021.08.007

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Drug-induced liver injury (DILI) is a major cause of drug failure in clinical trial and market withdrawal. Animal models are utilized to predict the risk of drug-induced liver injury. However, due to species differences, the accuracy of animal models is poor. Multiple human-derived hepatotoxic prediction models have been developed to assess this potential risk. This article reviews commonly used in vitro hepatotoxic models, as well as the latest improvement of hepatocyte culture protocols, especially hepatic co-culture system and 3D culture system in order to improve the accuracy of hepatotoxic risk prediction, which may also guide the liver toxicity mechanistic investigation in clinic. 

Potential health benefits of resveratrol: a pharmacokinetics-caused conundrum

WANG Yaya, CHU Zixuan, YANG Junling, Olajide E. Olaleye, HE Rongrong, LI Muzi, CHENG Chen, LI Chuan

2021, 26(8):  931-954.  doi:10.12092/j.issn.1009-2501.2021.08.008

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Resveratrol (3,5,4'-trihydroxy-trans-stilbene) was first identified from white hellebore (Veratrum grandiflorum) root and began to attract interest when its presence in red wine and cardiovascular activities were reported, leading to speculation of its contribution to the 'French paradox'. Besides the cardiovascular protection, potential health benefits of resveratrol include calorie restriction-like effects, cancer prevention and adjunctive therapy, and neuroprotection. In order to achieve translational applications of these potential benefits, pharmacokinetic research was performed for plasma pharmacokinetics and related disposition of orally dosed resveratrol. This paper summarizes the known human pharmacokinetic characteristics of resveratrol after oral administration and various attempts to improve its systemic exposure level from the perspectives of systemic exposure and in vivo process. However, available pharmacokinetic data of resveratrol has raised conundrums that limit translating potential benefits to clinics: (1) differences between the unchanged resveratrol used in bioactivity studies and its major circulating forms (i.e., metabolites) after dosing; (2) resveratrol's test concentrations used to exert in vitro bioactivities related to the benefits significantly higher than the compound's clinically achievable concentrations; (3) resveratrol's concentrations achievable (estimated from the pharmacokinetics) from doses used to produce in vivo efficacy significantly lower than the effective concentrations found in studies of related action mechanism (suggesting unreliability of test mechanism). In the last part of this review, we provide recommendations for future pharmacokinetic investigations of resveratrol, including a more systematic investigation of systemic exposure to resveratrol metabolites, their access to in vivo loci responsible for the benefits, and their disposition in target cells; an investigation of colon-luminal exposure to resveratrol and its metabolites for accessing colonic microbiota; and a multi-compound pharmacokinetic investigation of red wine. 

Metabolic regulation and drug target discovery researches in China: Progress and prospect 

HAO Haiping

2021, 26(8):  955-963.  doi:10.12092/j.issn.1009-2501.2021.08.009

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Metabolic regulation is an important mechanism by which organisms adapt to changes in the internal and external environment. Metabolic small molecules function as versatile messengers involved in signaling networks and organ crosstalk, which carries great implications for understanding physiological processes, revealing disease mechanisms and discovering drug targets. In this review, we present an overview of the main progresses in metabolic regulation and drug target discovery researches in China, and look forward to its future direction, which may provide a reference for the drug development endeavor based on metabolic regulation.

Applications of BGUSs inhibition in tumor prevention and chemotherapy

WU Rongrong, CHEN Zhiqiang, JIA Yifei, CHEN Hongqi, WANG Panpan, YAN Ru

2021, 26(8):  964-974.  doi:10.12092/j.issn.1009-2501.2021.08.010

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Bacterial β-glucuronidases (BGUSs) are an important type of hydrolase produced by gut microbiota and play an important role in tumor development and chemotherapy by deconjugating a large number of endogenous and exogenous glucuronides. In recent years, BGUSs inhibition has emerged as a promising approach to reduce cancer risk and alleviate gastrointestinal toxicity of chemotherapy drugs. However, a growing body of evidence underlines great genetic and structural diversity, functional promiscuity, and varied inhibition propensity of BGUSs, which have posed enormous challenges to identifying BGUSs involved in a specific pathophysiological or pharmacological process and developing effective inhibitors. In this review, we summarize the latest advances in structure and function of BGUSs and review the findings of BGUSs-mediated carcinogen reactivation and deconjugation of chemotherapy drugs in recent years, as well as the discovery of BGUSs inhibitors and preclinical investigation of their applications in cancer prevention and drug therapy. Finally, we discuss the prospects of BGUSs inhibition as a new strategy for tumor prevention and drug therapy.