AAPS PharmSci最新文献_第8页

Aerosolization of lipoplexes using AERx Pulmonary Delivery System. 使用AERx肺输送系统雾化脂丛。

AAPS PharmSci Pub Date : 2002-01-01 DOI: 10.1208/ps040313

Deepa Deshpande, James Blanchard, Sudarshan Srinivasan, Dallas Fairbanks, Jun Fujimoto, Teiji Sawa, Jeanine Wiener-Kronish, Hans Schreier, Igor Gonda

{"title":"Aerosolization of lipoplexes using AERx Pulmonary Delivery System.","authors":"Deepa Deshpande, James Blanchard, Sudarshan Srinivasan, Dallas Fairbanks, Jun Fujimoto, Teiji Sawa, Jeanine Wiener-Kronish, Hans Schreier, Igor Gonda","doi":"10.1208/ps040313","DOIUrl":"https://doi.org/10.1208/ps040313","url":null,"abstract":"The lung represents an attractive target for delivering gene therapy to achieve local and potentially systemic delivery of gene products. The objective of this study was to evaluate the feasibility of the AERx Pulmonary Delivery System for delivering nonviral gene therapy formulations to the lung. We found that \"naked\" DNA undergoes degradation following aerosolization through the AERx nozzle system. However, DNA formulated with a molar excess of cationic lipids (lipoplexes) showed no loss of integrity. In addition, the lipoplexes showed no significant change in particle size, zeta (zeta) potential, or degree of complexation following extrusion. The data suggest that complexation with cationic lipids had a protective effect on the formulation following extrusion. In addition, there was no significant change in the potency of the formulation as determined by a transfection study in A-549 cells in culture. We also found that DNA formulations prepared in lactose were aerosolized poorly. Significant improvements in aerosolization efficiency were seen when electrolytes such as NaCl were added to the formulation. In conclusion, the data suggest that delivery of lipoplexes using the AERx Pulmonary Delivery System may be a viable approach for pulmonary gene therapy.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 3","pages":"E13"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040313","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22103972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 33

Detection of MDR1 single nucleotide polymorphisms C3435T and G2677T using real-time polymerase chain reaction: MDR1 single nucleotide polymorphism genotyping assay. 实时聚合酶链反应检测MDR1单核苷酸多态性C3435T和G2677T: MDR1单核苷酸多态性基因分型试验

AAPS PharmSci Pub Date : 2002-01-01 DOI: 10.1208/ps040429

Pengfei Song, Shen Li, Bernd Meibohm, A Osama Gaber, Marsha R Honaker, Malak Kotb, Charles R Yates

{"title":"Detection of MDR1 single nucleotide polymorphisms C3435T and G2677T using real-time polymerase chain reaction: MDR1 single nucleotide polymorphism genotyping assay.","authors":"Pengfei Song, Shen Li, Bernd Meibohm, A Osama Gaber, Marsha R Honaker, Malak Kotb, Charles R Yates","doi":"10.1208/ps040429","DOIUrl":"https://doi.org/10.1208/ps040429","url":null,"abstract":"The objective of this study was to develop a real-time polymerase chain reaction (PCR) method to detect MDR1 (human multidrug resistance gene) single nucleotide polymorphisms (SNPs) C3435T and G2677T. C3435T and G2677T are linked to MDR1*2, which is associated with enhanced efflux activity in vitro. Using the Smart Cycler, an allele-specific real-time PCR-based genotyping method was developed to detect C3435T and G2677T. The MDR1 genotype of human genomic DNA templates was determined by direct DNA sequencing. PCR reactions for genotyping C3435T and G2677T by using allele-specific primers were conducted in separate tubes. An additional nucleotide mismatch at the third position from the 3' end of each allele-specific primer was used to abrogate nonspecific PCR amplification. The fluorescence emitted by SYBR Green I was monitored to detect formation of specific PCR products. PCR growth curves exceeding the threshold cycle were considered positive. Fluorescence melt-curve analysis was used to corroborate results from PCR growth curves. Using PCR growth curves, our assay accurately determined hetero- and homozygosity for C3435T and G2677T. Genotype assignments based on PCR growth curve, melt-curve analysis, agarose gel electrophoresis, and direct DNA sequencing results of PCR products were in perfect agreement. We have developed a rapid MDR1 genotyping method that can be used to assess the contribution of MDR1*2 to pharmacokinetic and pharmacodynamic variability of P-glycoprotein substrates.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E29"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040429","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22296909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 22

Introduction: pharmaceutics and drug delivery. 简介:制药和药物输送。

AAPS PharmSci Pub Date : 2002-01-01 DOI: 10.1208/ps040443

Bruce Aungst

{"title":"Introduction: pharmaceutics and drug delivery.","authors":"Bruce Aungst","doi":"10.1208/ps040443","DOIUrl":"https://doi.org/10.1208/ps040443","url":null,"abstract":"This theme issue of AAPS PharmSci is primarily intended to capture the contents of presentations made at the AAPS Pharmaceutics and Drug Delivery Conference held in April 2002. This meeting was the first conference sponsored by AAPS to focus on bringing to participants the latest information in the fields of drug delivery technology and pharmaceutics. The scientific presentations made at the meeting, and the follow up articles appearing in this issue represent the leading edge of pharmaceutical sciences. This journal issue is therefore also intended to provide a state-of-the-science synopsis of some of the problems facing pharmaceutical scientists today, as well as the approaches being investigated as possible solutions to those problems. As drug discovery processes have evolved in recent years, it has become increasingly common that the physicochemical and biopharmaceutical properties of new drug candidates are such that the development of bioavailable and stable dosage forms can be difficult. In many organizations pharmaceutics has become an integral component of the drug discovery process, so as to improve the properties of drug candidates entering development, reduce the failure rate of drugs in development and to improve the efficiency of development. And drug delivery has never had as important a role in bringing new medicines to patients, and in improving the effectiveness, safety, or compliance of older medicines, as now. Drug delivery technologies are constantly evolving and improving to breech the biological barriers separating drugs from their target sites.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E43"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040443","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22297996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Monitoring intracellular pH changes in response to osmotic stress and membrane transport activity using 5-chloromethylfluorescein. 利用5-氯甲基荧光素监测细胞内pH值变化对渗透胁迫和膜运输活性的响应。

AAPS PharmSci Pub Date : 2002-01-01 DOI: 10.1208/ps040421

Aline Salvi, J Mark Quillan, Wolfgang Sadée

{"title":"Monitoring intracellular pH changes in response to osmotic stress and membrane transport activity using 5-chloromethylfluorescein.","authors":"Aline Salvi, J Mark Quillan, Wolfgang Sadée","doi":"10.1208/ps040421","DOIUrl":"https://doi.org/10.1208/ps040421","url":null,"abstract":"Intracellular free H+ concentration (pHi) responds to numerous extracellular stimuli. The use of fluorescent indicator dyes to measure pHi is strongly influenced by the ability of target cells to retain activated dye within the cytoplasmic compartment. Here, 3 pH-sensitive indicator dye - acetoxymethyl (AM) esters of SNARF-1 and BCECF, and the thiol-reactive 5-chloromethyfluorescein (CMFDA) - were examined for monitoring pHi. The stability of pH measurements was strongly affected by temperature, cell type, indicator dye, and use of transport inhibitors to prevent dye export. Cellular retention of CMFDA, which forms covalent complexes, was sufficient to permit monitoring of transient pHi changes over extended time periods in a multi-well plate assay format. In human embryonic kidney (HEK293) and Chinese hamster ovary (CHO) cells, increasing osmotic pressure caused a significant rise in pHi. In contrast, activation of native or transfected beta-adrenergic, cholinergic, and d and m opioid receptors did not measurably affect pHi in HEK293 cells. Decreases in pHi were observed in CHO cells expressing the human H+/peptide transporter PEPT1 upon addition of dipeptide substrates. The use of CMFDA in multi-well formats should facilitate study of osmotic and transport activity and screening for drugs that affect pHi.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E21"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040421","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22298249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 28

The effect of alkylpolyglycoside surfactants on the crystallization of spray-dried salbutamol sulphate: a GravimetricNear-Infrared Spectroscopy Study. 烷基聚糖苷表面活性剂对喷雾干燥硫酸沙丁胺醇结晶的影响:重量-近红外光谱研究。

AAPS PharmSci Pub Date : 2002-01-01 DOI: 10.1208/ps040316

Angela Columbano, Graham Buckton, Philip Wikeley

{"title":"The effect of alkylpolyglycoside surfactants on the crystallization of spray-dried salbutamol sulphate: a GravimetricNear-Infrared Spectroscopy Study.","authors":"Angela Columbano, Graham Buckton, Philip Wikeley","doi":"10.1208/ps040316","DOIUrl":"https://doi.org/10.1208/ps040316","url":null,"abstract":"This study monitored the effect of a series of structurally related surfactants on the crystallization of amorphous salbutamol sulphate. Amorphous salbutamol sulphate was prepared by spray drying from a solution in water and in the presence of various alkylpolyglycosides (APGs) at different concentrations. The particles were then analyzed using isothermal microcalorimetry and water vapor sorption (Dynamic Vapour Sorption, DVS) analysis combined with near-infrared spectroscopy (DVS-NIR). Both isothermal microcalorimetry and DVS-NIR were able to detect the transition from the amorphous to the crystalline state. The presence of APG surfactants modified the shape of the crystallization peak obtained using isothermal microcalorimetry. The gravimetric study combined with NIR revealed that while the crystallization was similar for the particles with or without surfactant, there was a great difference in the release of water from the newly formed crystal. In the presence of some of the surfactants tested, salbutamol sulphate released the water much faster than in the absence of surfactant. These results helped to explain the differences found in the isothermal microcalorimeter data. Differences were observed in the shapes of the NIR water peaks related to water due to the presence of the surfactant. In conclusion, the use of DVS combined with NIR has helped to analyze and understand the effect of APGs on the crystallization of amorphous salbutamol sulphate.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 3","pages":"E16"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040316","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22103900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Quantitative comparison of functional screening by measuring intracellular Ca2+ with radioligand binding at recombinant human dopamine receptors. 通过测量细胞内Ca2+与重组人多巴胺受体放射配体结合的功能筛选的定量比较。

AAPS PharmSci Pub Date : 2002-01-01 DOI: 10.1208/ps040431

Matthias U Kassack

{"title":"Quantitative comparison of functional screening by measuring intracellular Ca2+ with radioligand binding at recombinant human dopamine receptors.","authors":"Matthias U Kassack","doi":"10.1208/ps040431","DOIUrl":"https://doi.org/10.1208/ps040431","url":null,"abstract":"The purpose of this study was to test whether screening at dopamine receptors performed with a recently described functional assay for G-protein coupled receptors (GPCRs) provides data that correlate significantly with radioligand binding data in the literature, thus possibly allowing researchers to replace radioligand binding with nonradioactive functional screening. Human dopamine receptors hD1 and hD2L (representing Gs [hD1] or Gi [hD2L] coupled GPCRs) were recombinantly expressed in human embryonic kidney (HEK293) cells. Cells were loaded with Oregon Green 488 BAPTA-1/AM and evenly distributed in 384 well plates. Seventeen test compounds were screened for agonistic activity by injection into the cell suspension and monitoringH of intracellular Ca2+ with a fluorescence microplate reader. Then, standard agonists (100nM SKF38393 for hD1, 30nM quinpirole for hD2L) were injected into wells preincubated with test compounds (screening for antagonism). Injection of various agonists resulted in a concentration-dependent increase in fluorescence. Further, preincubation of antagonists with dopamine receptor expressing cells inhibits concentration-dependent the agonist-induced increase in fluorescence. Calculated apparent functional Ki values correlate with radioligand binding data in the literature (r2 = 0.7796 for D1, r2 = 0.7743 for D2). The correlation between apparent functional Ki values and radioligand binding data for the 17 tested compounds suggests that screening of test compounds at dopamine receptors with the functional Ca2+ assay can replace radioligand binding studies. Furthermore, besides apparent Ki values, information about agonistic or antagonistic properties of a test compound can be obtained with the functional Ca2+ assay.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E31"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040431","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22296911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Pharmacodynamic modeling of chemotherapeutic effects: application of a transit compartment model to characterize methotrexate effects in vitro. 化疗效应的药效学模型：应用转运隔室模型描述甲氨蝶呤的体外效应。

AAPS PharmSci Pub Date : 2002-01-01 DOI: 10.1208/ps040442

Evelyn D Lobo, Joseph P Balthasar

{"title":"Pharmacodynamic modeling of chemotherapeutic effects: application of a transit compartment model to characterize methotrexate effects in vitro.","authors":"Evelyn D Lobo, Joseph P Balthasar","doi":"10.1208/ps040442","DOIUrl":"10.1208/ps040442","url":null,"abstract":"The time course of chemotherapeutic effect is often delayed relative to the time course of chemotherapeutic exposure. In many cases, this delay is difficult to characterize mathematically through the use of standard pharmacodynamic models. In the present work, we investigated the relationship between methotrexate (MTX) exposure and the time course of MTX effects on tumor cell growth in culture. Two cancer cell lines, Ehrlich ascites cells and sarcoma 180 cells, were exposed for 24 hours to MTX concentrations that varied more than 700-fold (0.19-140 micro g/mL). Viable cells were counted on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 20, 22, and 24 for Ehrlich ascites cells and on days 1, 2, 3, 5, 7, 9, 11, 13, 14, 15, 17, 19, and 21 for sarcoma 180 cells, through the use of a tetrazolium assay. Although MTX was removed 24 hours after application, cell numbers reached nadir values more than 100 hours after MTX exposure. Data from each cell line were fitted to 3 pharmacodynamic models of chemotherapeutic cell killing: a cell cycle phase-specific model, a phase-nonspecific model, and a transit compartment model (based on the general model recently reported by Mager and Jusko, Clin Pharmacol Ther. 70:210-216, 2001). The transit compartment model captured the data much more accurately than the standard pharmacodynamic models, with correlation coefficients ranging from 0.86 to 0.999. This report shows the successful application of a transit compartment model for characterization of the complex time course of chemotherapeutic effects; such models may be very useful in the development of optimization strategies for cancer chemotherapy.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E42"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751331/pdf/12248_2008_Article_44217.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22298110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data? 从体外数据预测体内药物相互作用时，抑制剂的浓度应该是多少?

AAPS PharmSci Pub Date : 2002-01-01 DOI: 10.1208/ps040425

Kiyomi Ito, Koji Chiba, Masato Horikawa, Michi Ishigami, Naomi Mizuno, Jun Aoki, Yasumasa Gotoh, Takafumi Iwatsubo, Shin-ichi Kanamitsu, Motohiro Kato, Iichiro Kawahara, Kayoko Niinuma, Akiko Nishino, Norihito Sato, Yuko Tsukamoto, Kaoru Ueda, Tomoo Itoh, Yuichi Sugiyama

{"title":"Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data?","authors":"Kiyomi Ito, Koji Chiba, Masato Horikawa, Michi Ishigami, Naomi Mizuno, Jun Aoki, Yasumasa Gotoh, Takafumi Iwatsubo, Shin-ichi Kanamitsu, Motohiro Kato, Iichiro Kawahara, Kayoko Niinuma, Akiko Nishino, Norihito Sato, Yuko Tsukamoto, Kaoru Ueda, Tomoo Itoh, Yuichi Sugiyama","doi":"10.1208/ps040425","DOIUrl":"https://doi.org/10.1208/ps040425","url":null,"abstract":"When the metabolism of a drug is competitively or noncompetitively inhibited by another drug, the degree of in vivo interaction can be evaluated from the [I]u/Ki ratio, where [I]u is the unbound concentration around the enzyme and Ki is the inhibition constant of the inhibitor. In the present study, we evaluated the metabolic inhibition potential of drugs known to be inhibitors or substrates of cytochrome P450 by estimating their [I]u/Ki ratio using literature data. The maximum concentration of the inhibitor in the circulating blood ([I]max), its maximum unbound concentration in the circulating blood ([I]max,u), and its maximum unbound concentration at the inlet to the liver ([I]in,max,u) were used as [I]u, and the results were compared with each other. In order to calculate the [I]u/Ki ratios, the pharmacokinetic parameters of each drug were obtained from the literature, together with their reported Ki values determined in in vitro studies using human liver microsomes. For most of the drugs with a calculated [I]in,max,u/Ki ratio less than 0.25, which applied to about half of the drugs investigated, no in vivo interactions had been reported or \"no interaction\" was reported in clinical studies. In contrast, the [I]max,u/Ki and [I]max/Ki ratio was calculated to be less than 0.25 for about 90% and 65% of the drugs, respectively, and more than a 1.25-fold increase was reported in the area under the concentration-time curve of the co-administered drug for about 30% of such drugs. These findings indicate that the possibility of underestimation of in vivo interactions (possibility of false-negative prediction) is greater when [I]max,u or [I]max values are used compared with using [I]in,max,u values.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E25"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040425","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22298253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 78

Pharmacokinetic/pharmacodynamic integration in drug development and dosage-regimen optimization for veterinary medicine. 药物动力学/药效学在兽医药物开发和剂量-方案优化中的整合。

AAPS PharmSci Pub Date : 2002-01-01 DOI: 10.1208/ps040438

Pierre-Louis Toutain

{"title":"Pharmacokinetic/pharmacodynamic integration in drug development and dosage-regimen optimization for veterinary medicine.","authors":"Pierre-Louis Toutain","doi":"10.1208/ps040438","DOIUrl":"10.1208/ps040438","url":null,"abstract":"Pharmacokinetic (PK)/pharmacodynamic (PD) modeling is a scientific tool to help developers select a rational dosage regimen for confirmatory clinical testing. This article describes some of the limitations associated with traditional dose-titration designs (parallel and crossover designs) for determining an appropriate dosage regimen. It also explains how a PK/PD model integrates the PK model (describing the relationship between dose, systemic drug concentrations, and time) with the PD model (describing the relationship between systemic drug concentration and the effect vs time profile) and a statistical model (particularly, the intra- and interindividual variability of PK and/or PD origin). Of equal importance is the utility of these models for promoting rational drug selection on the basis of effectiveness and selectivity. PK/PD modeling can be executed using various approaches, such as direct versus indirect response models and parametric versus nonparametric models. PK/PD concepts can be applied to individual dose optimization. Examples of the application of PK/PD approaches in veterinary drug development are provided, with particular emphasis given to nonsteroidal anti-inflammatory drugs. The limits of PK/PD approaches include the development of appropriate models, the validity of surrogate endpoints, and the acceptance of these models in a regulatory environment.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E38"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751327/pdf/12248_2008_Article_44165.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22298107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of MRP4 and MRP5 in biology and chemotherapy. MRP4 和 MRP5 在生物学和化疗中的作用。

AAPS PharmSci Pub Date : 2002-01-01 DOI: 10.1208/ps040314

J Sampath, M Adachi, S Hatse, L Naesens, J Balzarini, R M Flatley, L H Matherly, J D Schuetz

{"title":"Role of MRP4 and MRP5 in biology and chemotherapy.","authors":"J Sampath, M Adachi, S Hatse, L Naesens, J Balzarini, R M Flatley, L H Matherly, J D Schuetz","doi":"10.1208/ps040314","DOIUrl":"10.1208/ps040314","url":null,"abstract":"Nucleotide efflux (especially cyclic nucleotides) from a variety of mammalian tissues, bacteria, and lower eukaryotes has been studied for several decades. However, the molecular identity of these nucleotide efflux transporters remained elusive, despite extensive knowledge of their kinetic properties and inhibitor profiles. Identification of the subfamily of adenosine triphosphate (ATP) binding cassette transporters, multidrug resistance protein (MRP) subfamily, permitted rapid advances because some recently identified MRP family members transport modified nucleotide analogs (ie, chemotherapeutic agents). We first identified, MRP4, based on its ability to efflux antiretroviral compounds, such as azidothymidine monophosphate (AZT-MP) and 9-(2-phosphonyl methoxyethyl) adenine (PMEA), in drug-resistant and also in transfected cell lines. MRP5, a close structural homologue of MRP4 also transported PMEA. MRP4 and MRP5 confer resistance to cytotoxic thiopurine nucleotides, and we demonstrate MRP4 expression varies among acute lymphoblastic leukemias, suggesting this as a factor in response to chemotherapy with these agents. The ability of MRP4 and MRP5 to transport 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) suggests they may play a biological role in cellular signaling by these nucleotides. Finally, we propose that MRP4 may also play a role in hepatic bile acid homeostasis because loss of the main bile acid efflux transporter, sister of P-glycoprotein (SPGP) aka bile-salt export pump (BSEP), leads to a strong compensatory upregulation in MRP4 expression. Cumulatively, these studies reveal that the ATP-binding cassette (ABC) transporters MRP4 and MRP5 have a unique role in biology and in chemotherapeutic response.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 3","pages":"E14"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751353/pdf/12248_2008_Article_43022.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22103973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0