ADMET and DMPK最新文献_第9页

Drug-like Properties and Fraction Lipophilicity Index as a combined metric 药物样性质和分数亲脂性指数作为联合度量

IF 2.5

ADMET and DMPK Pub Date : 2021-10-08 DOI: 10.5599/admet.1022

A. Tsantili-Kakoulidou, V. Demopoulos

{"title":"Drug-like Properties and Fraction Lipophilicity Index as a combined metric","authors":"A. Tsantili-Kakoulidou, V. Demopoulos","doi":"10.5599/admet.1022","DOIUrl":"https://doi.org/10.5599/admet.1022","url":null,"abstract":"Fraction Lipophicity Index (FLI) has been developed as a composite drug-like metric combining log P and log D in a weighted manner. In the present study, an extended data set confirmed the previously established drug-like FLI range 0-8 using two calculation systems for log P/log D assessment, the freeware MedChem Designer and ClogP. The dataset was split into two classes according to the percentage of fraction absorbed (%FA) - class 1 including drugs with high to medium absorption levels and class 2 including poorly absorbed drugs. The FLI and FLI-C (ClogP based FLI) drug-like range covers 92 % and 91 % of class 1 drugs, respectively. Using MlogP, a narrower drug-like FLI-M range 0-7 was established, covering 91 % of class 1 drugs. The dependence of the degree of ionization to intrinsic lipophilicity within the FLI (FLI-C, FLI-M) drug-like range as well as the inter-relation between the other Ro5 properties (Mw, HD, HA) was explored to define drug-like / non-drug-like combinations as a safer alternative to single properties for drug candidates’ prioritization. In this sense, we propose a combined metric of Mw and the number of polar atoms (Mw/NO) to account for both size and polarity. Setting the value 50 as cutoff, a distinct differentiation between class 1 and class 2 drugs was obtained with Mw/NO>50 for more than 70 % of class 1 drugs, while the opposite was observed for class 2 drugs.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"71 1","pages":"177 - 190"},"PeriodicalIF":2.5,"publicationDate":"2021-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86246549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8

Investigating antimicrobial features and drug interactions of sedoanalgesics in intensive care unit: an experimental study 研究重症监护病房中sedo镇痛药的抗菌特性和药物相互作用:一项实验研究

IF 2.5

ADMET and DMPK Pub Date : 2021-09-06 DOI: 10.5599/admet.1042

Ozge Unlu, Emre Bingul, S. Kesi̇ci̇, M. Demirci

{"title":"Investigating antimicrobial features and drug interactions of sedoanalgesics in intensive care unit: an experimental study","authors":"Ozge Unlu, Emre Bingul, S. Kesi̇ci̇, M. Demirci","doi":"10.5599/admet.1042","DOIUrl":"https://doi.org/10.5599/admet.1042","url":null,"abstract":"Study Objective Aim of this study was to evaluate antimicrobial effects and interaction between analgesic combinations of fentanyl citrate, dexmedetomidine hydrochloride and tramadol hydrochloride on Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Candida albicans which are some of the most common nosocomial infection related microorganisms. Design In vitro prospective study. Setting University Clinical Microbiology Laboratory. Measurements In order to evaluate in vitro antimicrobial effects and interaction between analgesic combinations, tramadol hydrochloride, fentanyl citrate and dexmedetomidin were used against S. aureus ATCC 29213, K. pneumoniae, E. coli ATCC 25922, P. aeruginosa ATCC 27853 and C. albicans ATCC 10231 standard strains by microdilution method. Main Results According to microdilution assays tramadol has shown the most efficient antimicrobial activity also it has been observed that 10 μg/ml concentrated dexmedetomidine has antimicrobial effects on S. aureus, K. pneumoniae and P. aeruginosa. Fentanyl has displayed evident inhibitory potency on the pathogens except for Klebsiella pneumoniae, nevertheless our predefined minimum concentration inhibited growth by 9.5 %. Fentanyl and dexmedetomidine together exhibited more antimicrobial effect on P. aeruginosa and E. coli growth. Additionally, when the three drugs examined together, microbial inhibition occurred more than expected on E. coli again and also on C. albicans growth. Conclusions Our results revealed the antimicrobial properties and synergy with the different combinations of fentanyl, dexmedetomidine and tramadol against the most common nosocomial infection agents in the ICU. This is the first study in the literature looking into the microbial “interactions” of opioids and sedative drugs but more research is needed in order to define clinico-laboratory correlation.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"57 1","pages":"219 - 226"},"PeriodicalIF":2.5,"publicationDate":"2021-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81509092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Are we ready to design oral PROTACs®? 我们准备好设计口服PROTACs®了吗?

IF 2.5

ADMET and DMPK Pub Date : 2021-08-31 DOI: 10.5599/admet.1037

Diego García Jiménez, M. Rossi Sebastiano, G. Caron, G. Ermondi

{"title":"Are we ready to design oral PROTACs®?","authors":"Diego García Jiménez, M. Rossi Sebastiano, G. Caron, G. Ermondi","doi":"10.5599/admet.1037","DOIUrl":"https://doi.org/10.5599/admet.1037","url":null,"abstract":"PROTACs® are expected to strongly impact the future of drug discovery. Therefore, in this work we firstly performed a statistical study to highlight the distribution of E3 ligases and POIs collected in PROTAC-DB, the main online database focused on degraders. Moreover, since the emerging technology of protein degradation deals with large and complex chemical structures, the second part of the paper focuses on how to set up a property-based design strategy to obtain oral degraders. For this purpose, we calculated a pool of seven previously ad hoc selected 2D descriptors for the 2258 publicly available degraders in PROTAC-DB (average values: MW= 972.9 Da, nC= 49.5, NAR= 4.5, PHI= 17.3, nHDon= 4.5, nHAcc= 17.7 and TPSA= 240 Å2) and compared them to a dataset of 50 bRo5 orally approved drugs. Then, a chemical space based on nC, PHI and TPSA was built and subregions with optimal permeability and bioavailability were identified. Bioavailable degraders (ARV-110 and ARV-471) tend to be closer to the Ro5 region, using mainly semi-rigid linkers. Permeable degraders, on the other hand, are placed in an average central region of the chemical space but chameleonicity could allow them to be located closer to the two Arvinas compounds.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"16 1","pages":"243 - 254"},"PeriodicalIF":2.5,"publicationDate":"2021-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90062833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 10

Current state and future of 3D bioprinted models for cardiovascular research and drug development 用于心血管研究和药物开发的3D生物打印模型的现状和未来

IF 2.5

ADMET and DMPK Pub Date : 2021-08-25 DOI: 10.5599/admet.951

L. Polonchuk, C. Gentile

引用次数: 1

Lost in modelling and simulation? 迷失在建模和仿真中?

IF 2.5

ADMET and DMPK Pub Date : 2021-03-20 DOI: 10.5599/ADMET.923

K. Sugano

引用次数: 18

Synthesis and biological activity of 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide derivatives 2-[6-甲基-4-(噻坦-3-基氧基)嘧啶-2-基硫]乙酰肼衍生物的合成及生物活性研究

IF 2.5

ADMET and DMPK Pub Date : 2021-02-18 DOI: 10.5599/admet.941

S. Meshcheryakova, Alina Shumadalova, O. Beylerli, I. Gareev

{"title":"Synthesis and biological activity of 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide derivatives","authors":"S. Meshcheryakova, Alina Shumadalova, O. Beylerli, I. Gareev","doi":"10.5599/admet.941","DOIUrl":"https://doi.org/10.5599/admet.941","url":null,"abstract":"The synthesis and antimicrobial evaluation of new 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide derivatives was investigated. According to the literature, there are a lot of antimicrobial agents among the pyrimidines and hydrazides, and therefore it seems promising to use 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide as a base object for synthesizing new biologically active substances. 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide was obtained by the hydrazinolysis of ethyl thioacetate, using a 3-fold molar excess of 85 % hydrazine hydrate in ethanol, at room temperature. Interaction of 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide with ketones during boiling in ethanol yielded N-ylidenehydrazides. The solid obtained by concentration was collected, and then purified by recrystallization. The new compounds were characterized by 1H, 13C NMR, IR spectroscopy and elemental analysis. The antibacterial and antifungal activities of the new compounds were analysed using agar diffusion and tenfold broth (pH 7.2 – 7.4) dilution methods, in comparison with the clinical used drugs, ceftriaxone and Pimafucin. The structure–activity studies showed that, depending on the nature of the hydrazide fragment, the newly synthesized compounds exhibited varying degrees of microbial inhibition. Within the same series the antimicrobial activity depends on the nature of the substituent attached to the benzene ring. The investigation of antibacterial screening data revealed that the compounds N′-[1-(4-aminophenyl)ethylidene]-2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide, N′-[1-(4-hydroxyphenyl)ethylidene]-2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide, N′-[1- (2,5-dihydroxyphenyl) ethylidene]-2-[6-methyl-4-(thietan-3-yloxy)-pyrimidin-2-ylthio]acetohydrazide were found to be more potent than the other synthesized analogues.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"11 1","pages":"167 - 176"},"PeriodicalIF":2.5,"publicationDate":"2021-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79825763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of pharmacokinetics of warfarin from validated pharmacokinetic-pharmacodynamic model 从有效的药动学-药效学模型评价华法林的药动学

IF 2.5

ADMET and DMPK Pub Date : 2021-01-18 DOI: 10.5599/admet.909

K. Sridharan, R. Al Banna, Aysha A Husain

{"title":"Evaluation of pharmacokinetics of warfarin from validated pharmacokinetic-pharmacodynamic model","authors":"K. Sridharan, R. Al Banna, Aysha A Husain","doi":"10.5599/admet.909","DOIUrl":"https://doi.org/10.5599/admet.909","url":null,"abstract":"Background Pharmacokinetics of warfarin has not been described in our population. We derived the pharmacokinetic parameters from a validated pharmacokinetic-pharmacodynamic model. Methods Patients receiving warfarin for at least 6 months were recruited and their demographic characteristics, prothrombin time international normalized ratio (PT-INR), warfarin doses and concomitant drugs were collected. Using a validated pharmacokinetic-pharmacodynamic model, we predicted maximum plasma concentration (Cmax), total clearance (CL), volume of distribution (Vd) and elimination rate (k). Warfarin sensitive index (WSI) and warfarin composite measures (WCM) were estimated from the dose and INR values. Liver weight was predicted using validated formula. Results Two-hundred and twenty patients were recruited. The following were the predicted pharmacokinetic parameters: Cmax (mg/L) was 5.8 (0.4); k (L/day) was 1 (0.1); CL (L/day) was 2.1 (0.2); and Vd (L) was 7.6 (0.2). Patients with Cmax and elimination rate outside the mean+1.96 SD had significantly lower WSI and higher WCM. Significant correlations were observed between Cmax with CL, Vd, and k of warfarin. Significant correlations were also observed between CL and Vd of warfarin with liver weight of the study participants. Conclusion We predicted pharmacokinetic parameters of warfarin from the validated pharmacokinetic-pharmacodynamic model in our population. More studies are needed exploring the relationship between various pharmacodynamic indices of warfarin and pharmacokinetic parameters of warfarin.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"12 1","pages":"143 - 149"},"PeriodicalIF":2.5,"publicationDate":"2021-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79663248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A concise review on lipidomics analysis in biological samples 生物样品中的脂质组学分析综述

IF 2.5

ADMET and DMPK Pub Date : 2020-12-08 DOI: 10.5599/admet.913

R. Addepalli, R. Mullangi

引用次数: 2

In vitro pH dependent passive transport of ketoprofen and metformin 体外pH依赖性酮洛芬和二甲双胍的被动转运

IF 2.5

ADMET and DMPK Pub Date : 2020-12-08 DOI: 10.5599/admet.916

A. Elezovic, Amina Marić, Amila Biščević, J. Hadžiabdić, Selma Škrbo, S. Špirtović-Halilović, O. Rahić, E. Vranić, A. Elezović

{"title":"In vitro pH dependent passive transport of ketoprofen and metformin","authors":"A. Elezovic, Amina Marić, Amila Biščević, J. Hadžiabdić, Selma Škrbo, S. Špirtović-Halilović, O. Rahić, E. Vranić, A. Elezović","doi":"10.5599/admet.916","DOIUrl":"https://doi.org/10.5599/admet.916","url":null,"abstract":"The kinetics of passive transport of ketoprofen and metformin, as model substances for high and low permeability, respectively, across the artificial membrane under the influence of the pH of donor solution was investigated. There was an upward trend in the apparent permeation coefficient (Papp) of ketoprofen with the decrease in pH to a value close to pKa. At the pH value below pKa the permeation coefficient had lower value, due to the higher retention of ketoprofen in the artificial membrane. Metformin is a low permeable compound, and the highest permeation values were recorded at pH 7.4. Two dissociation constants determine that metformin at physiological pH exists as a hydrophilic cationic molecule, i.e. predominantly in ionized form. At pH values below 2.8, metformin mainly exists in diprotonated form, and it was, thus, very poorly permeable. The highest retention, i.e. affinity of both ketoprofen and metformin to the membrane, was at the lowest pH values, which is explained by different mechanisms. At higher pH values of donor compartment the substances showed significantly less affinity to the membrane. The obtained values of apparent permeation coefficients at studied pH values showed good correlation with the obtained experimental values by other in vitro methods.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"10 1","pages":"57 - 68"},"PeriodicalIF":2.5,"publicationDate":"2020-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89029479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Intestinal absorption of BCS class II drugs administered as nanoparticles: A review based on in vivo data from intestinal perfusion models 以纳米颗粒形式给药的BCS II类药物的肠道吸收:基于肠道灌注模型体内数据的综述

IF 2.5

ADMET and DMPK Pub Date : 2020-09-17 DOI: 10.5599/admet.881

D. Dahlgren, E. Sjögren, H. Lennernäs

引用次数: 8