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Quantitative assessment of the relevance of organic-aniontransporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics

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Journal of Pharmaceutical Analysis 2023年第6期13卷 660-672页

作者： Ji-Hun Jang Seung-Hyun Jeong Yong-Bok Lee Department of pharmacy College of PharmacyChonnam National UniversityGwangju61186Republic of Korea Department of pharmacy College of PharmacySunchon National UniversitySuncheon-si57922Republic of Korea

Fexofenadine is useful in various allergic disease treatment.However,the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking.This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmacokinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability.Polymorphisms of the organic-anion-transporting-polypeptide(OATP)1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity.Therefore,modeling was performed using fexofenadine oral exposure data according to the OATP1B1-and 2B1-polymorphisms.OATP1B1 and 2B1 were identified as effective covariates of clearance(CL/F)and distribution volume(V/F)-CL/F,respectively,in fexofenadine pharmacokinetic variability.CL/F and average steady-state plasma concentration of fexofenadine differed by up to 2.17-and 2.20-folds,respectively,depending on the OATP1B1 polymorphism.Among the individuals with different OATP2B1 polymorphisms,the CL/F and V/F differed by up to 1.73-and 2.00-folds,respectively.Ratio of the areas under the curves following single-and multiple-administrations,and the cumulative ratio were significantly different between OATP1B1-and 2B1-polymorphism groups.Based on quantitative prediction comparison through a model-based approach,OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability.Based on the established pharmacokineticpharmacodynamic relationship,the difference in fexofenadine efficacy according to genetic polymorphisms of OATP1B1 and 2B1 was 1.25-and 0.87-times,respectively,and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well.This population pharmacometrics study will be a very useful starting point for fexofenadine precision medicine.

关键词： OATP1B1 OATP2B1 Fexofenadine Population pharmacometrics Genetic polymorphism

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Alterations of Gefitinib Pharmacokinetics by Co-administration of Herbal Medications in Rats

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Chinese Journal of Integrative Medicine 2018年第6期24卷 460-466页

作者： Kwon-Yeon Weon Min Gi Kim Soyoung Shin Tae Hwan Kim Sang Hoon Joo Eunsook Ma Seok Won Jeong Sun Dong Yoo Yu Seok Youn Beom Soo Shin college of pharmacy Catholic University of Daegu School of pharmacy Sungkyunkwan University college of pharmacy Wonkwang University

Objective： To evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib （Iressae） and the oriental medications Guipi Decoction （归脾汤, GPD, Guibi-tang in Korean） and Bawu Decoction （八物汤, BWD, Palmul-tang in Korean）. Methods： Methylceliulose （MC, control）, GPD （1,200 mg/kg）, or BWD （6,000 mg/kg） was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefitinib （10 mg/kg） was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments. To examine the effects of the multiple doses of the herbal medicines, gefltinib （10 mg/kg） was orally administered following 7 consecutive days of the administration of MC or each herbal medicine. The plasma concentrations of gefitinib were determined with liquid chromatography-tandem mass spectrometry assay. The plasma concentration-time profiles of gefitinib were analyzed with a noncompartmental analysis. Results： Gefitinib was rapidly absorbed and showed a mono- exponential decline with an elimination half-life of 3.7-4.1 h. The pharmacokinetics of gefitinib was not affected by GPD pretreatment. However, a significantly lower maximum plasma concentration （Crux, P〈0.05） and area under the curve （P〈0.05）, and a delayed time to reach Cmax （Tmax, P〈0.01） were observed in both single- and multiple- dose BWD-pretreated rats compared with the control rats. Conclusions： BWD and not GPD might delay and interfere with gefitinib absorption. Further evaluations of the clinical significance of these findings are needed.

关键词： herb-drug interaction pharmacokinetics gefitinib Guipi Decoction Bawu Decoction

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Effect of La^(3+) on seed germination and seedling growth of Salvia miltiorrhiza

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Journal of Rare Earths 2018年第8期36卷 898-902页

作者： Qingxin Sun Liangyue Sun Shangcai Feng Shaofen Guo college of pharmacy Guangdong Pharmaceutical University college of pharmacy Linyi University

The purpose of this study is to determine the effect of La^3＋ solution on seed germination and seedling growth of Salvia miltiorrhiza. Different concentrations of La^3＋ were used on seed by soaking treated to determine which concentration is the most suitable for the growth of S. miltiorrhiza. Results show that the low concentration of La^3＋ displays the promotion effect on S. miltiorrhiza seed germination rate and germination potential, and the promotion effect reaches the highest level when the concentration of La^3＋solution is 30 mg/L, the germination index and vigor index are the highest in 20 mg/L, and it can also increase the contents of soluble sugar, soluble protein and chlorophyll. Meanwhile, the activity of antioxidant enzyme system（CAT and SOD） are improved, thus the photosynthesis and resistance of plant are enhanced. On the contrary, when the La^3＋ concentration is high, La^3＋ can inhibit plant growth. Thus La^3＋ displays the ＂homesis effect＂ on S. miltiorrhiza growth.

关键词： Salvia miltiorrhiza La^3＋ Seed germination Seedling growth Rare earths

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Remembering your A, B, C’s: Alzheimer’s disease and ABCA1

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Acta Pharmaceutica Sinica B 2022年第3期12卷 995-1018页

作者： Cutler T.Lewandowski Megan S.Laham Gregory R.J.Thatcher Department of Pharmaceutical Sciences University of Illinois College of PharmacyChicagoIL 60612USA Department of Pharmacology and Toxicology University of Arizona College of PharmacyTucsonAZ 85721USA

The function of ATP binding cassette protein A1(ABCA1)is central to cholesterol mobilization.Reduced ABCA1 expression or activity is implicated in Alzheimer’s disease(AD)and other disorders.Therapeutic approaches to boost ABCA1 activity have yet to be translated successfully to the clinic.The risk factors for AD development and progression,including comorbid disorders such as type2 diabetes and cardiovascular disease,highlight the intersection of cholesterol transport and inflammation.Upregulation of ABCA1 can positively impact APOE lipidation,insulin sensitivity,peripheral vascular and blood-brain barrier integrity,and anti-inflammatory signaling.Various strategies towards ABCA1-boosting compounds have been described,with a bias toward nuclear hormone receptor(NHR)agonists.These agonists display beneficial preclinical effects;however,important side effects have limited development.In particular,ligands that bind liver X receptor(LXR),the primary NHR that controls ABCA1 expression,have shown positive effects in AD mouse models;however,lipogenesis and unwanted increases in triglyceride production are often observed.The longstanding approach,focusing on LXRβvs.LXRa selectivity,is over-simplistic and has failed.Novel approaches such as phenotypic screening may lead to small molecule NHR modulators that elevate ABCA1 function without inducing lipogenesis and are clinically translatable.

关键词： Alzheimer’s disease Cardiovascular disease Cholesterol Drug discovery Liver X receptor Nuclear hormone receptor Type 2 diabetes

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Construction and imaging of a neurovascular unit model

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Neural Regeneration Research 2022年第8期17卷 1685-1694页

作者： Taiwei Dong Min Li Feng Gao Peifeng Wei Jian Wang college of pharmacy Shaanxi University of Chinese MedicineXianyangShaanxi ProvinceChina college of pharmacy Chengdu University of Traditional Chinese MedicineChengduSichuan ProvinveChina

In 2001,the concept of the neurovascular unit was introduced at the Stroke Progress Review Group meeting.The neurovascular unit is an important element of the health and disease status of blood vessels and nerves in the central nervous system.Since then,the neurovascular unit has attracted increasing interest from research teams,who have contributed greatly to the prevention,treatment,and prognosis of stroke and neurodegenerative diseases.However,additional research is needed to establish an efficient,low-cost,and low-energy in vitro model of the neurovascular unit,as well as enable noninvasive observation of neurovascular units in vivo and in vitro.In this review,we first summarize the composition of neurovascular units,then investigate the efficacy of different types of stem cells and cell culture methods in the construction of neurovascular unit models,and finally assess the progress of imaging methods used to observe neurovascular units in recent years and their positive role in the monitoring and investigation of the mechanisms of a variety of central nervous system diseases.

关键词： 3D printing blood-brain barrier computational biology encephalopathy imaging techniques microfluidic on-chip methods nerve cell co-culture neurovascular unit review stem cells

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Identification of poliumoside metabolites in rat plasma, urine, bile, and intestinal bacteria with UPLC/Q-TOF-MS

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Chinese Journal of Natural Medicines 2018年第11期16卷 871-880页

作者： QIAN Hao YU Fang-Jun LU Dan-Yi WU Bao-Jian ZHANG Xing-Wang WANG Huan MA Zhi-Guo college of pharmacy Jinan University

Poliumoside is representative of phenylethanoid glycosides, which are widely found in many plants. Poliumoside is also regarded as the main active component of Callicarpa kwangtungensis Chun(CK), though its oral bioavailability in rat is extremely low(0.69%) and its in vivo and in vitro metabolism has not yet been systematically investigated. In the present study, an ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry(UPLC/Q-TOF-MS) method was employed to identify the metabolites and investigate the metabolic pathways of poliumoside in rat after oral administration 1.5 g·kg–1 of poliumoside. As a result, a total of 34 metabolites(30 from urine, 17 from plasma, and 4 from bile) and 9 possible metabolic pathways(rearrangment, reduction, hydration, hydrolyzation, dehydration, methylation, hydroxylation, acetylation, and sulfation) were proposed in vivo. The main metabolite, acteoside, was quantified after incubated with rat intestinal bacteria in vitro. In conclusion, the present study systematically explored the metabolites of poliumoside in vivo and in vitro, proposing metabolic pathways that may be significant for further metabolic studies of poliumoside.

关键词： Poliumoside 老鼠代谢物肠的细菌 UPLC/Q-TOF-MS

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Anti-aging properties of Ribes fasciculatum in Caenorhabditis elegans

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Chinese Journal of Natural Medicines 2016年第5期14卷 335-342页

作者： Hoon Jeon Dong Seok Cha Department of Oriental pharmacy College of Pharmacy Woosuk University

The present study investigated the effects and underlying mechanism of ethylacetate fraction of Ribes fasciculatum(ERF) on the lifespan and stress tolerance using a Caenorhabditis elegans model. The longevity activity of ERF was determined by lifespan assay under normal culture condition. The survival rate of nematodes under various stress conditions was assessed to validate the effects of ERF on the stress tolerance. To determine the antioxidant potential of ERF, the superoxide dismutase(SOD) activities and intracellular reactive oxygen species(ROS) levels were investigated. The ERF-mediated change in SOD-3 expression was examined using GFP-expressing transgenic strain. The effects of ERF on the aging-related factors were investigated by reproduction assay and pharyngeal pumping assay. The intestinal lipofuscin levels of aged nematodes were also measured. The mechanistic studies were performed using selected mutant strains. Our results indicated that ERF showed potent lifespan extension effects on the wild-type nematode under both normal and various stress conditions. The ERF treatment also enhanced the activity and expression of superoxide dismutase(SOD) and attenuated the intracellular ROS levels. Moreover, ERF-fed nematodes showed decreased lipofuscin accumulation, indicating ERF might affect age-associated changes in C. elegans. The results of mechanistic studies indicated that there was no significant lifespan extension in ERF-treated daf-2, age-1, sir-2.1, and daf-16 null mutants, suggesting that they were involved in ERF-mediated lifespan regulation. In conclusion, R. fasciculatum confers increased longevity and stress resistance in C. elegans via SIR-2.1-mediated DAF-16 activation, dependent on the insulin/IGF signaling pathway.

关键词：秀丽隐杆线虫抗老化性能超氧化物歧化酶寿命试验应力条件绿色荧光蛋白 ERF 长寿命

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Complex formulations, simple techniques: Can 3D printing technology be the Midas touch in pharmaceutical industry?

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Asian Journal of Pharmaceutical Sciences 2019年第5期14卷 465-479页

作者： Shrawani Lamichhane Santosh Bashyal Taekwang Keum Gyubin Noh Jo Eun Seo Rakesh Bastola Jaewoong Choi Dong Hwan Sohn Sangkil Lee college of pharmacy Keimyung University

3 D printing is a method of rapid prototyping and manufacturing in which materials are deposited onto one another in layers to produce a three-dimensional object. Although 3 D printing was developed in the 1980 s and the technology has found widespread industrial applications for production from automotive parts to machine tools,its application in pharmaceutical area is still limited. However,the potential of 3 D printing in the pharmaceutical industry is now being recognized. The ability of 3 D printing to produce medications to exact specifications tailored to the needs of individual patients has indicated the possibility of developing personalized medicines. The technology allows dosage forms to be precisely printed in various shapes,sizes and textures that are difficult to produce using traditional techniques. However,there are various challenges associated with the proper application of3 D printing in the pharmaceutical sector which should be overcome to exploit the scope of this technology. In this review,an overview is provided on the various 3 D printing technologies used in fabrication of complex dosage forms along with their feasibility and limitations.

关键词： Three-dimensional printing Personalized medicine Fused deposition modeling Inkjet printing Complex formulations

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Network pharmacology and molecular docking study on the effect of Kaempferol in treatment of metabolic associated fatty liver disease

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Journal of Traditional Chinese Medicine 2022年第5期42卷 788-794页

作者： ZHOU Kaixuan ZHANG Dong BAO Huiwei LI Lijing college of pharmacy Changchun University of Chinese MedicineChangchun 130117China

OBJECTIVE: To study therapeutic effect of kaempferol on metabolic associated fatty liver disease(MAFLD) by network pharmacology and molecular docking combined with cell experiments. METHODS: First, use the Swiss Target Prediction database to predict the targets of kaempferol, and collect the targets of MAFLD through the Disgenet database and the Gene Cards database. Then, the common target of kaempferol and MAFLD was enriched and analyzed by the Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes, and the protein-protein interaction(PPI) network was constructed through the string database to obtain the key targets, and carry out molecular docking of key targets with kaempferol;In cell experiment, oleic acid induced steatosis in Hep G2 cells, which was intervened by kaempferol, the level of triglyceride(TG) was detected, the lipid deposition was observed by oil red O staining, and the protein expression was detected by Western blot. RESULTS: The results showed that there are 33 common targets for kaempferol and MAFLD. The biological process of GO is related to the regulation of protein kinase B, cell apoptosis, inflammatory factors, lipoxygenase, etc. Its action pathway is related to the phosphatidylinositol-3-kinase and protein kinase B(PI3K-AKT) signaling pathway, hypoxia-inducible factor 1 signaling pathway, forkhead box protein O signaling pathway, AMP-activated protein kinase signaling pathway, tumor necrosis factor signaling pathway, etc., the key targets are protein kinase B(AKT1), prostaglandin G/H synthase 2, matrix metalloproteinase-9, epidermal growth factor receptor, and the molecular docking of kaempferol with the four key targets shows good binding properties. Cell experiments show that kaempferol can reduce cell TG levels, reduce lipid deposition, increase the expression of PI3K, AKT, and beclin-1, and reduce the expression of caspase-3 and nuclear factor-kappa B. Kaempferol can treat MAFLD by regulating the PI3K-AKT signaling pathway to regulate cell autophagy, apoptosis, and inflammation

关键词： Metabolic associated fatty liver disease kaempferol network pharmacology molecular docking simulation protein kinase B protoonco-gene proteins c-akt signaling transduction

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A facile synthesis of cajaninstilbene acid and its derivatives

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Chinese Chemical Letters 2019年第8期30卷 1527-1529页

作者： Qi Chen Kuo Lu Chang Zheng Xiao-Fang Xu Jing Lin Wei-Min Chen college of pharmacy Jinan University

A four-step synthesis of methyl 6-formyl-2-hydroxy-4-methoxy-3-(3-methylbut-2-en-1-yl)benzoate(11)that can be used as building block for a facile synthesis of cajaninstilbene acid and its derivatives is reported.The synthesis of cajaninstilbene acid was accomplished in six steps with an overall yield of 20%starting from commercial materials by a synthesis whose key steps are TiCl4-mediated[3+3]cyclization and McMurry coupling.

关键词： Cajaninstilbene acid Synthesis Building block Derivatives

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