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.
{"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}
Diego García Jiménez, M. Rossi Sebastiano, G. Caron, G. Ermondi
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.
{"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}
In the last decade, 3D bioprinting technology has emerged as an innovative tissue engineering approach for regenerative medicine and drug development. This article aims at providing an overview about the most commonly used bioengineered tissues, focusing on 3D bioprinted cardiac cells and how they have been utilized for drug discovery and development. The review describes that, while this field is still developing, cardiovascular research may benefit from laboratory-engineered heart tissues built of specific cell types with precise 3D architecture mimicking the native cardiac microenvironment. It also describes the role played by regulatory agencies and potential commercialization pathways for direct translation from the bench to the bedside of studies using 3D bioprinted cardiac tissues.
{"title":"Current state and future of 3D bioprinted models for cardiovascular research and drug development","authors":"L. Polonchuk, C. Gentile","doi":"10.5599/admet.951","DOIUrl":"https://doi.org/10.5599/admet.951","url":null,"abstract":"In the last decade, 3D bioprinting technology has emerged as an innovative tissue engineering approach for regenerative medicine and drug development. This article aims at providing an overview about the most commonly used bioengineered tissues, focusing on 3D bioprinted cardiac cells and how they have been utilized for drug discovery and development. The review describes that, while this field is still developing, cardiovascular research may benefit from laboratory-engineered heart tissues built of specific cell types with precise 3D architecture mimicking the native cardiac microenvironment. It also describes the role played by regulatory agencies and potential commercialization pathways for direct translation from the bench to the bedside of studies using 3D bioprinted cardiac tissues.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"37 1","pages":"231 - 242"},"PeriodicalIF":2.5,"publicationDate":"2021-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80603102","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}
Over the past few decades, physiologically-based pharmacokinetic modelling (PBPK) has been anticipated to be a powerful tool to improve the productivity of drug discovery and development. However, recently, multiple systematic evaluation studies independently suggested that the predictive power of current oral absorption (OA) PBPK models needs significant improvement. There is some disagreement between the industry and regulators about the credibility of OA PBPK modelling. Recently, the editorial board of AMDET&DMPK has announced the policy for the articles related to PBPK modelling (Modelling and simulation ethics). In this feature article, the background of this policy is explained: (1) Requirements for scientific writing of PBPK modelling, (2) Scientific literacy for PBPK modelling, and (3) Middle-out approaches. PBPK models are a useful tool if used correctly. This article will hopefully help advance the science of OA PBPK models.
{"title":"Lost in modelling and simulation?","authors":"K. Sugano","doi":"10.5599/ADMET.923","DOIUrl":"https://doi.org/10.5599/ADMET.923","url":null,"abstract":"Over the past few decades, physiologically-based pharmacokinetic modelling (PBPK) has been anticipated to be a powerful tool to improve the productivity of drug discovery and development. However, recently, multiple systematic evaluation studies independently suggested that the predictive power of current oral absorption (OA) PBPK models needs significant improvement. There is some disagreement between the industry and regulators about the credibility of OA PBPK modelling. Recently, the editorial board of AMDET&DMPK has announced the policy for the articles related to PBPK modelling (Modelling and simulation ethics). In this feature article, the background of this policy is explained: (1) Requirements for scientific writing of PBPK modelling, (2) Scientific literacy for PBPK modelling, and (3) Middle-out approaches. PBPK models are a useful tool if used correctly. This article will hopefully help advance the science of OA PBPK models.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"141 1","pages":"75 - 109"},"PeriodicalIF":2.5,"publicationDate":"2021-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76800810","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}
S. Meshcheryakova, Alina Shumadalova, O. Beylerli, I. Gareev
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.
{"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}
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.
{"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}
Lipids are a complex and critical heterogeneous molecular entity, playing an intricate and key role in understanding biological activities and disease processes. Lipidomics aims to quantitatively define the lipid classes, including their molecular species. The analysis of the biological tissues and fluids are challenging due to the extreme sample complexity and occurrence of the molecular species as isomers or isobars. This review documents the overview of lipidomics workflow, beginning from the approaches of sample preparation, various analytical techniques and emphasizing the state-of-the-art mass spectrometry either by shotgun or coupled with liquid chromatography. We have considered the latest ion mobility spectroscopy technologies to deal with the vast number of structural isomers, different imaging techniques. All these techniques have their pitfalls and we have discussed how to circumvent them after reviewing the power of each technique with examples..
{"title":"A concise review on lipidomics analysis in biological samples","authors":"R. Addepalli, R. Mullangi","doi":"10.5599/admet.913","DOIUrl":"https://doi.org/10.5599/admet.913","url":null,"abstract":"Lipids are a complex and critical heterogeneous molecular entity, playing an intricate and key role in understanding biological activities and disease processes. Lipidomics aims to quantitatively define the lipid classes, including their molecular species. The analysis of the biological tissues and fluids are challenging due to the extreme sample complexity and occurrence of the molecular species as isomers or isobars. This review documents the overview of lipidomics workflow, beginning from the approaches of sample preparation, various analytical techniques and emphasizing the state-of-the-art mass spectrometry either by shotgun or coupled with liquid chromatography. We have considered the latest ion mobility spectroscopy technologies to deal with the vast number of structural isomers, different imaging techniques. All these techniques have their pitfalls and we have discussed how to circumvent them after reviewing the power of each technique with examples..","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"10 1","pages":"1 - 22"},"PeriodicalIF":2.5,"publicationDate":"2020-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86630545","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}
A. Elezovic, Amina Marić, Amila Biščević, J. Hadžiabdić, Selma Škrbo, S. Špirtović-Halilović, O. Rahić, E. Vranić, A. Elezović
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.
{"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}
An established pharmaceutical strategy to increase oral drug absorption of low solubility–high permeability drugs is to create nanoparticles of them. Reducing the size of the solid-state particles increases their dissolution and transport rate across the mucus barrier and the aqueous boundary layer. Suspensions of nanoparticles also sometimes behave differently than those of larger particles in the fed state. This review compares the absorption mechanisms of nano- and larger particles in the lumen at different prandial states, with an emphasis on data derived from in vivo models. Four BSC class II drugs—aprepitant, cyclosporine, danazol and fenofibrate—are discussed in detail based on information from preclinical intestinal perfusion models.
{"title":"Intestinal absorption of BCS class II drugs administered as nanoparticles: A review based on in vivo data from intestinal perfusion models","authors":"D. Dahlgren, E. Sjögren, H. Lennernäs","doi":"10.5599/admet.881","DOIUrl":"https://doi.org/10.5599/admet.881","url":null,"abstract":"An established pharmaceutical strategy to increase oral drug absorption of low solubility–high permeability drugs is to create nanoparticles of them. Reducing the size of the solid-state particles increases their dissolution and transport rate across the mucus barrier and the aqueous boundary layer. Suspensions of nanoparticles also sometimes behave differently than those of larger particles in the fed state. This review compares the absorption mechanisms of nano- and larger particles in the lumen at different prandial states, with an emphasis on data derived from in vivo models. Four BSC class II drugs—aprepitant, cyclosporine, danazol and fenofibrate—are discussed in detail based on information from preclinical intestinal perfusion models.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"23 1","pages":"375 - 390"},"PeriodicalIF":2.5,"publicationDate":"2020-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76171331","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}
The prediction of solubility of drugs usually calls on the use of several open-source/commercially-available computer programs in the various calculation steps. Popular statistics to indicate the strength of the prediction model include the coefficient of determination (r2), Pearson’s linear correlation coefficient (rPearson), and the root-mean-square error (RMSE), among many others. When a program calculates these statistics, slightly different definitions may be used. This commentary briefly reviews the definitions of three types of r2 and RMSE statistics (model validation, bias compensation, and Pearson) and how systematic errors due to shortcomings in solubility prediction models can be differently indicated by the choice of statistical indices. The indices we have employed in recently published papers on the prediction of solubility of druglike molecules were unclear, especially in cases of drugs from ‘beyond the Rule of 5’ chemical space, as simple prediction models showed distinctive ‘bias-tilt’ systematic type scatter.
{"title":"Do you know your r2?","authors":"A. Avdeef","doi":"10.5599/admet.888","DOIUrl":"https://doi.org/10.5599/admet.888","url":null,"abstract":"The prediction of solubility of drugs usually calls on the use of several open-source/commercially-available computer programs in the various calculation steps. Popular statistics to indicate the strength of the prediction model include the coefficient of determination (r2), Pearson’s linear correlation coefficient (rPearson), and the root-mean-square error (RMSE), among many others. When a program calculates these statistics, slightly different definitions may be used. This commentary briefly reviews the definitions of three types of r2 and RMSE statistics (model validation, bias compensation, and Pearson) and how systematic errors due to shortcomings in solubility prediction models can be differently indicated by the choice of statistical indices. The indices we have employed in recently published papers on the prediction of solubility of druglike molecules were unclear, especially in cases of drugs from ‘beyond the Rule of 5’ chemical space, as simple prediction models showed distinctive ‘bias-tilt’ systematic type scatter.","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"1 1","pages":"69 - 74"},"PeriodicalIF":2.5,"publicationDate":"2020-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91124434","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：