Cytochrome P450 (CYP) 2B6 belongs to the set of important hepatic drug-metabolizing CYPs. It makes up roughly 3%-6% of total hepatic CYP content and metabolizes several pharmaceuticals including bupropion, efavirenz, cyclophosphamide, pethidine, ketamine and propofol. The enzyme is susceptible to drug-drug interactions by enzyme induction and inhibition. In addition to drugs, CYP2B6 is able to both detoxify and bioactivate a number of procarcinogens and environmental agents including pesticides and herbicides. There is an extensive interindividual variability in the expression of CYP2B6, which is in part explained by extensive genetic polymorphism. CYP2B6 is one of the most polymorphic CYP genes in humans with over 100 described SNPs, numerous complex haplotypes and distinct ethnic and racial frequencies. This review summarizes the basic properties of CYP2B6 and the main characteristics of clinical relevance.
{"title":"Cytochrome P450 2B6: function, genetics, and clinical relevance.","authors":"Miia Turpeinen, Ulrich M Zanger","doi":"10.1515/dmdi-2012-0027","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0027","url":null,"abstract":"<p><p>Cytochrome P450 (CYP) 2B6 belongs to the set of important hepatic drug-metabolizing CYPs. It makes up roughly 3%-6% of total hepatic CYP content and metabolizes several pharmaceuticals including bupropion, efavirenz, cyclophosphamide, pethidine, ketamine and propofol. The enzyme is susceptible to drug-drug interactions by enzyme induction and inhibition. In addition to drugs, CYP2B6 is able to both detoxify and bioactivate a number of procarcinogens and environmental agents including pesticides and herbicides. There is an extensive interindividual variability in the expression of CYP2B6, which is in part explained by extensive genetic polymorphism. CYP2B6 is one of the most polymorphic CYP genes in humans with over 100 described SNPs, numerous complex haplotypes and distinct ethnic and racial frequencies. This review summarizes the basic properties of CYP2B6 and the main characteristics of clinical relevance.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"27 4","pages":"185-97"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31048260","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}
As of 2007, PLAVIX (the original brand name of clopidogrel) had been the second top-selling drug in the world and is, presently, prescribed and marketed in nearly 110 countries. Clopidogrel is currently the thienopyridine of choice for dual antiplatelet therapy (in combination with aspirin) in patients with the full spectrum of acute coronary syndrome and in those undergoing percutaneous coronary intervention and stenting. In a plethora of pharmacogenomic studies on PLAVIX, it has been shown that clopidogrel is a prodrug that requires biotransformation to an active metabolite by CYP450 enzymes (mainly CYP2C19) and paraoxonase 1 (PON-1). There is signifi cant inter-individual variability in the response to PLAVIX, with up to 40 % of patients being classifi ed as non-responders, poor responders, or resistant to this drug. Pharmacogenomic information on PLAVIX reveals that genetic polymorphisms of CYP enzymes (most commonly CYP2C19*2), PON-1, and also the ABCB 1 transporter contribute to variation in the response of individual patients to the drug. In March 2010, the Food and Drug Administration (FDA) released a “ boxed warning ” on PLAVIX addressing the need for pharmacogenomic testing (for detecting CYP2C19 loss-of-function polymorphisms) to identify patients ’ altered PLAVIX metabolism, and thus their risk for a suboptimal clinical response to this drug. On the basis of an expanding database, and as an approach to the FDA boxed warning, the American College of Cardiology Foundation/ American Heart Association-convened writing committee developed an evidence-based guideline, “ Recommendations for Practice, ” in July 2010. These documents were validated in France in October 2010 and the SmPC (Summary of Product Characteristics) of PLAVIX was updated accordingly by the French regulatory agency (AFSSAPS).
{"title":"Need for pharmacogenomic information also for generic medications: recommendation of the European Society of Pharmacogenomics and Theranostics (ESPT).","authors":"Gérard Seist","doi":"10.1515/dmdi-2012-0010","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0010","url":null,"abstract":"As of 2007, PLAVIX (the original brand name of clopidogrel) had been the second top-selling drug in the world and is, presently, prescribed and marketed in nearly 110 countries. Clopidogrel is currently the thienopyridine of choice for dual antiplatelet therapy (in combination with aspirin) in patients with the full spectrum of acute coronary syndrome and in those undergoing percutaneous coronary intervention and stenting. In a plethora of pharmacogenomic studies on PLAVIX, it has been shown that clopidogrel is a prodrug that requires biotransformation to an active metabolite by CYP450 enzymes (mainly CYP2C19) and paraoxonase 1 (PON-1). There is signifi cant inter-individual variability in the response to PLAVIX, with up to 40 % of patients being classifi ed as non-responders, poor responders, or resistant to this drug. Pharmacogenomic information on PLAVIX reveals that genetic polymorphisms of CYP enzymes (most commonly CYP2C19*2), PON-1, and also the ABCB 1 transporter contribute to variation in the response of individual patients to the drug. In March 2010, the Food and Drug Administration (FDA) released a “ boxed warning ” on PLAVIX addressing the need for pharmacogenomic testing (for detecting CYP2C19 loss-of-function polymorphisms) to identify patients ’ altered PLAVIX metabolism, and thus their risk for a suboptimal clinical response to this drug. On the basis of an expanding database, and as an approach to the FDA boxed warning, the American College of Cardiology Foundation/ American Heart Association-convened writing committee developed an evidence-based guideline, “ Recommendations for Practice, ” in July 2010. These documents were validated in France in October 2010 and the SmPC (Summary of Product Characteristics) of PLAVIX was updated accordingly by the French regulatory agency (AFSSAPS).","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"27 2","pages":"119"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30696090","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}
Pedro Dorado, Fernando de Andrés, María Eugenia G Naranjo, Eva M Peñas-Lledó, Idilio González, Antonio P González, Alfredo de la Rubia, Adrián Llerena
Background: Aripiprazole (ARI) is an antipsychotic drug that is metabolized to dehydroaripiprazole (DARI) by CYP2D6. Because of the large interindividual variability in ARI and DARI plasma concentrations, therapeutic drug monitoring may be of use in psychiatric patients during treatment with ARI. The aim of the present study was to develop a simple and reliable method for the quantitative determination of ARI and DARI in plasma using liquid-liquid extraction and reverse-phase high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The method was tested in psychiatric patients during regular treatment with ARI.
Methods: Separation was by the liquid-liquid method, and UV detection at 254 nm. Linear responses for ARI and DARI were obtained between 2 and 1000 ng/mL, and precision assays were lower than 10.4 for both analytes.
Results: Lower limit of quantification and detection were 1 and 0.38 ng/mL for ARI and 0.78 and 0.44 ng/mL for DARI, respectively. The method was successfully applied to plasma samples drawn from 22 patients with concentrations ranging between 2 and 189 ng/mL for ARI and between 11 and 359 ng/mL for DARI.
Conclusions: The chromatographic method developed has been demonstrated to be sensitive and reliable for the measurement of ARI and DARI simultaneously in human plasma, and the present method represents an alternative procedure to evaluate plasma concentration in patients during treatment with ARI.
{"title":"High-performance liquid chromatography method using ultraviolet detection for the quantification of aripiprazole and dehydroaripiprazole in psychiatric patients.","authors":"Pedro Dorado, Fernando de Andrés, María Eugenia G Naranjo, Eva M Peñas-Lledó, Idilio González, Antonio P González, Alfredo de la Rubia, Adrián Llerena","doi":"10.1515/dmdi-2012-0016","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0016","url":null,"abstract":"<p><strong>Background: </strong>Aripiprazole (ARI) is an antipsychotic drug that is metabolized to dehydroaripiprazole (DARI) by CYP2D6. Because of the large interindividual variability in ARI and DARI plasma concentrations, therapeutic drug monitoring may be of use in psychiatric patients during treatment with ARI. The aim of the present study was to develop a simple and reliable method for the quantitative determination of ARI and DARI in plasma using liquid-liquid extraction and reverse-phase high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The method was tested in psychiatric patients during regular treatment with ARI.</p><p><strong>Methods: </strong>Separation was by the liquid-liquid method, and UV detection at 254 nm. Linear responses for ARI and DARI were obtained between 2 and 1000 ng/mL, and precision assays were lower than 10.4 for both analytes.</p><p><strong>Results: </strong>Lower limit of quantification and detection were 1 and 0.38 ng/mL for ARI and 0.78 and 0.44 ng/mL for DARI, respectively. The method was successfully applied to plasma samples drawn from 22 patients with concentrations ranging between 2 and 189 ng/mL for ARI and between 11 and 359 ng/mL for DARI.</p><p><strong>Conclusions: </strong>The chromatographic method developed has been demonstrated to be sensitive and reliable for the measurement of ARI and DARI simultaneously in human plasma, and the present method represents an alternative procedure to evaluate plasma concentration in patients during treatment with ARI.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"27 3","pages":"165-70"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30995775","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}
Pedro Dorado, Esther Machín, Fernando de Andrés, María-Eugenia Naranjo, Eva M Peñas-Lledó, Adrián Llerena
Background: Losartan is metabolized to losartan carboxylic acid (E-3174) by the polymorphic cytochrome CYP2C9. The aim of the study was to develop a high-performance liquid chromatographic (HPLC) method with fluorescence detection for simultaneously measuring losartan and its metabolite E-3174 in urine to evaluate the losartan urinary metabolic ratio (MR: losartan/E-3174) for CYP2C9 phenotyping in humans.
Methods: The compounds were separated in a reversed-phase chromatographic column and detected by fluorescence at a wavelength of 250 nm for excitation and of 370 nm for emission.
Results: No analytical interferences with endogenous compounds were found, and the extraction recoveries were over 88%. Limits of quantification of 2 ng mL-1 for losartan and 5 ng mL-1 for E-3174 were achieved, as well as good reproducibility with coefficients of variation of <9% in all cases. Analyses with the present HPLC method show significant differences (p<0.05) in losartan MRs between the four CYP2C9 genotype groups in 13 Spanish healthy volunteers.
Conclusions: The method developed is simple and affordable, as well as sensitive and reliable to calculate the MR. Therefore, it appears to be useful for CYP2C9 phenotyping using losartan as a drug test in populations, such as Hispanics with different allele combinations.
背景:氯沙坦被多态细胞色素CYP2C9代谢为氯沙坦羧酸(E-3174)。本研究的目的是建立高效液相色谱(HPLC)荧光检测同时测定尿中氯沙坦及其代谢物E-3174的方法，评估氯沙坦尿代谢比(MR: losartan/E-3174)对人CYP2C9表型的影响。方法:采用反相色谱柱分离，荧光检测，激发波长为250 nm，发射波长为370 nm。结果:内源化合物对分析无干扰，提取回收率在88%以上。氯沙坦和E-3174分别获得了2 ng mL-1和5 ng mL-1的定量限，且变异系数重复性好。结论:所建立的方法简便、经济、mr计算灵敏、可靠，可用于不同等位基因组合人群(如西班牙裔)中氯沙坦作为药物试验的CYP2C9表型分析。
{"title":"Development of a HPLC method for the determination of losartan urinary metabolic ratio to be used for the determination of CYP2C9 hydroxylation phenotypes.","authors":"Pedro Dorado, Esther Machín, Fernando de Andrés, María-Eugenia Naranjo, Eva M Peñas-Lledó, Adrián Llerena","doi":"10.1515/dmdi-2012-0018","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0018","url":null,"abstract":"<p><strong>Background: </strong>Losartan is metabolized to losartan carboxylic acid (E-3174) by the polymorphic cytochrome CYP2C9. The aim of the study was to develop a high-performance liquid chromatographic (HPLC) method with fluorescence detection for simultaneously measuring losartan and its metabolite E-3174 in urine to evaluate the losartan urinary metabolic ratio (MR: losartan/E-3174) for CYP2C9 phenotyping in humans.</p><p><strong>Methods: </strong>The compounds were separated in a reversed-phase chromatographic column and detected by fluorescence at a wavelength of 250 nm for excitation and of 370 nm for emission.</p><p><strong>Results: </strong>No analytical interferences with endogenous compounds were found, and the extraction recoveries were over 88%. Limits of quantification of 2 ng mL-1 for losartan and 5 ng mL-1 for E-3174 were achieved, as well as good reproducibility with coefficients of variation of <9% in all cases. Analyses with the present HPLC method show significant differences (p<0.05) in losartan MRs between the four CYP2C9 genotype groups in 13 Spanish healthy volunteers.</p><p><strong>Conclusions: </strong>The method developed is simple and affordable, as well as sensitive and reliable to calculate the MR. Therefore, it appears to be useful for CYP2C9 phenotyping using losartan as a drug test in populations, such as Hispanics with different allele combinations.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"27 4","pages":"217-33"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30998048","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}
Truly personalized healthcare facilitating the management of personal health drives a fundamental change not just in what is known but also in how we think of ourselves and the way we are living, thus redefining our society (1) . We have to prepare now – just in time! – for all the various organizational changes ahead of us. The political will is there. However, the real paradigm shift depends on the willingness to restructure our current policies, to support knowledge transfer to maximize benefit to public health, and – most important – to change our minds. So far, all stakeholders including policy-makers and the private sector are struggling to translate the emerging knowledge into public health. Public Health Genomics (PHG) is the area of public health ensuring that scientific advances in genomics ( “ from cell ... ” ) triggered by innovative technologies are timely, effectively and responsibly translated into health policies and practice for the benefit of population health ( “ ... to society ” ). But, what evidence emerging from basic sciences needs to be translated ? New insights are being obtained from genomics, proteomics, transcriptomics, metabolomics, epigenomics, microbiomics, and other “ omics ” technologies. As these data are integrated through the use of information and communication technologies (ICT), we are at the edge of achieving an understanding of the systems biology and systems biomedicine of human health and disease that also incorporates environmental contributions such as lifestyle, toxic agents, social and economic factors, as well as health systems determinants. In this way, we can begin to envisage new approaches to the promotion and management of human health across the entire life course of an individual. Indeed, we can now consider a future involving truly personalized healthcare in which technological advances are placed at the service of population health. The evidence we now require to demonstrate the benefit of new technologies will need to follow a new paradigm, however. What is required is an assessment of individual benefit rather than overall effects in large populations or even subpopulations of patients. Thus, public health assessment and evaluation tools must now address concepts such as “ personal utility ” rather than clinical utility. These developments and the involvement of the patient brought forward the concept of P4 (predictive, preventive, personalized and participatory) medicine serving already as a blueprint for Public Health Genomics to prepare healthcare systems and policy-makers for this shift in our approach to healthcare. The P4 medicine is no longer a vision, it is a mission! We can and should go beyond the P4 medicine and recognize in the light of a “ systems approach to public health ” , that (2) : – Common complex diseases can be considered in terms of a constellation of “ rare ” diseases, each of which reflects a complex biological system. – We are moving away from a traditional class
{"title":"Public Health Genomics and personalized healthcare: a pipeline from cell to society.","authors":"Angela Brand","doi":"10.1515/dmdi-2012-0028","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0028","url":null,"abstract":"Truly personalized healthcare facilitating the management of personal health drives a fundamental change not just in what is known but also in how we think of ourselves and the way we are living, thus redefining our society (1) . We have to prepare now – just in time! – for all the various organizational changes ahead of us. The political will is there. However, the real paradigm shift depends on the willingness to restructure our current policies, to support knowledge transfer to maximize benefit to public health, and – most important – to change our minds. So far, all stakeholders including policy-makers and the private sector are struggling to translate the emerging knowledge into public health. Public Health Genomics (PHG) is the area of public health ensuring that scientific advances in genomics ( “ from cell ... ” ) triggered by innovative technologies are timely, effectively and responsibly translated into health policies and practice for the benefit of population health ( “ ... to society ” ). But, what evidence emerging from basic sciences needs to be translated ? New insights are being obtained from genomics, proteomics, transcriptomics, metabolomics, epigenomics, microbiomics, and other “ omics ” technologies. As these data are integrated through the use of information and communication technologies (ICT), we are at the edge of achieving an understanding of the systems biology and systems biomedicine of human health and disease that also incorporates environmental contributions such as lifestyle, toxic agents, social and economic factors, as well as health systems determinants. In this way, we can begin to envisage new approaches to the promotion and management of human health across the entire life course of an individual. Indeed, we can now consider a future involving truly personalized healthcare in which technological advances are placed at the service of population health. The evidence we now require to demonstrate the benefit of new technologies will need to follow a new paradigm, however. What is required is an assessment of individual benefit rather than overall effects in large populations or even subpopulations of patients. Thus, public health assessment and evaluation tools must now address concepts such as “ personal utility ” rather than clinical utility. These developments and the involvement of the patient brought forward the concept of P4 (predictive, preventive, personalized and participatory) medicine serving already as a blueprint for Public Health Genomics to prepare healthcare systems and policy-makers for this shift in our approach to healthcare. The P4 medicine is no longer a vision, it is a mission! We can and should go beyond the P4 medicine and recognize in the light of a “ systems approach to public health ” , that (2) : – Common complex diseases can be considered in terms of a constellation of “ rare ” diseases, each of which reflects a complex biological system. – We are moving away from a traditional class","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"27 3","pages":"121-3"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31009226","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}
*Corresponding author: Prof. Angela Brand, MD, PhD, MPH, Coordinator PHGEN, Institute for Public Health Genomics, Cluster of Genetics and Cell Biology, Faculty of Health, Medicine and Life Science, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands, Phone: + 31-646705062, E-mail: a.brand@maastrichtuniversity.nl Angela Brand: Institute for Public Health Genomics , Research Schools GROW and CAPHRI, Maastricht University, Maastricht , The Netherlands Jonathan A. Lal : Institute for Public Health Genomics , Research Schools GROW and CAPHRI, Maastricht University, Maastricht , The Netherlands
{"title":"European Best Practice Guidelines for Quality Assurance, Provision and Use of Genome-based Information and Technologies: the 2012 Declaration of Rome.","authors":"Angela Brand, Jonathan A Lal","doi":"10.1515/dmdi-2012-0026","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0026","url":null,"abstract":"*Corresponding author: Prof. Angela Brand, MD, PhD, MPH, Coordinator PHGEN, Institute for Public Health Genomics, Cluster of Genetics and Cell Biology, Faculty of Health, Medicine and Life Science, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands, Phone: + 31-646705062, E-mail: a.brand@maastrichtuniversity.nl Angela Brand: Institute for Public Health Genomics , Research Schools GROW and CAPHRI, Maastricht University, Maastricht , The Netherlands Jonathan A. Lal : Institute for Public Health Genomics , Research Schools GROW and CAPHRI, Maastricht University, Maastricht , The Netherlands","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"27 3","pages":"177-82"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30876485","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}
{"title":"Report from the European Society of Pharmacogenomics and Theranostics (ESPT) Inaugural Symposium 2011 in Bled.","authors":"Irena Prodan Žitnik, Janja Marc","doi":"10.1515/dmdi-2012-0004","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0004","url":null,"abstract":"No abstract available.","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"27 1","pages":"55-6"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30705735","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: Pharmacokinetic parameters, drug bioavailability, and biological activities depend on the mechanisms of interaction with serum albumin. In this study, the binding properties as well as mechanisms of interaction of chloroquine with bovine serum albumin (BSA) were investigated.
Methods: The binding of chloroquine with BSA was carried out using a microcalorimetric approach. The mechanism of binding, the number of binding molecules as well as changes of BSA upon complexation with chloroquine were investigated.
Results: The binding isotherms indicated a variable number of binding sites of chloroquine on one molecule of BSA. At lower temperatures, larger numbers of binding sites were available for chloroquine, these decrease by increasing the temperature. The binding constant of chloroquine with BSA varied from 9.4×10³ M⁻¹ at 25°C to 5.7×10³ M⁻¹ at 40°C. Chloroquine showed temperature-dependent binding affinity, with stronger affinity at lower temperature. By increasing the temperature, from 25°C to 40°C, the binding affinity was decreased by approximately 60% of its value.
Conclusions: Chloroquine showed weak binding affinity with BSA. The weak binding affinity of chloroquine with BSA is important in determining the drug-drug interactions at the binding sites of BSA. The presence of stronger binding ligands, e.g., chloramphenicol, tetracyclines or diclofenac, can compete with chloroquine for its binding sites, and therefore lowers its serum albumin binding. This study will be helpful in understanding the binding properties of mechanisms of interaction of chloroquine with BSA.
{"title":"Analysis of the molecular interactions and complexation of chloroquine with bovine serum albumin.","authors":"Mahmoud Kandeel, Yukio Kitade","doi":"10.1515/DMDI.2011.030","DOIUrl":"https://doi.org/10.1515/DMDI.2011.030","url":null,"abstract":"<p><strong>Background: </strong>Pharmacokinetic parameters, drug bioavailability, and biological activities depend on the mechanisms of interaction with serum albumin. In this study, the binding properties as well as mechanisms of interaction of chloroquine with bovine serum albumin (BSA) were investigated.</p><p><strong>Methods: </strong>The binding of chloroquine with BSA was carried out using a microcalorimetric approach. The mechanism of binding, the number of binding molecules as well as changes of BSA upon complexation with chloroquine were investigated.</p><p><strong>Results: </strong>The binding isotherms indicated a variable number of binding sites of chloroquine on one molecule of BSA. At lower temperatures, larger numbers of binding sites were available for chloroquine, these decrease by increasing the temperature. The binding constant of chloroquine with BSA varied from 9.4×10³ M⁻¹ at 25°C to 5.7×10³ M⁻¹ at 40°C. Chloroquine showed temperature-dependent binding affinity, with stronger affinity at lower temperature. By increasing the temperature, from 25°C to 40°C, the binding affinity was decreased by approximately 60% of its value.</p><p><strong>Conclusions: </strong>Chloroquine showed weak binding affinity with BSA. The weak binding affinity of chloroquine with BSA is important in determining the drug-drug interactions at the binding sites of BSA. The presence of stronger binding ligands, e.g., chloramphenicol, tetracyclines or diclofenac, can compete with chloroquine for its binding sites, and therefore lowers its serum albumin binding. This study will be helpful in understanding the binding properties of mechanisms of interaction of chloroquine with BSA.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"27 1","pages":"41-6"},"PeriodicalIF":0.0,"publicationDate":"2011-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2011.030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40128921","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}
Pub Date : 2011-01-01Epub Date: 2011-11-07DOI: 10.1515/DMDI.2011.024
Julia Grottker, Albert Rosenberger, Gerhard Burckhardt, Yohannes Hagos
Background: The transport of endogenous and exogenous organic cations across the plasma membrane of cells is mediated by multispecific organic cation transporters (OCTs), and the multidrug and toxin extrusion (MATE) transporters. MATE belongs to the SLC47 transporter family consisting of only two members, MATE1 and MATE2-K. MATE2-K is exclusively expressed in the kidney at the apical membrane of proximal tubular epithelial cells. MATE1 is highly expressed in the kidney, liver, skeletal muscle and also in adrenal glands, testes and heart. MATE1 exchanges organic cations against protons both in influx as well as in efflux modes.
Methods: Here, we examined the interaction of 25 antineoplastic agents with human MATE1. We generated stably transfected MATE1-HEK293 cells and determined the inhibition of MATE1-mediated [(3)H]1-methyl-4-phenylpyridinium (MPP) uptake by the antineoplastic agents.
Results: We found a significant inhibition of MATE1-mediated MPP uptake by several antineoplastic agents and pH dependent IC(50)values for mitoxantrone (7.8 μM at pH 7.4 and 0.6 μM at pH 8.5) as well as for irinotecan (4.4 μM at pH 7.4 and 1.1 μM at pH 8.5), respectively.
Conclusions: We suggest that hMATE1 could play a role in chemosensitivity of tumor cells. In addition, hepatic and renal MATE1 could potentially be involved in drug-drug-interactions as well as in drug metabolism and excretion during chemotherapy.
{"title":"Interaction of human multidrug and toxin extrusion 1 (MATE1) transporter with antineoplastic agents.","authors":"Julia Grottker, Albert Rosenberger, Gerhard Burckhardt, Yohannes Hagos","doi":"10.1515/DMDI.2011.024","DOIUrl":"https://doi.org/10.1515/DMDI.2011.024","url":null,"abstract":"<p><strong>Background: </strong>The transport of endogenous and exogenous organic cations across the plasma membrane of cells is mediated by multispecific organic cation transporters (OCTs), and the multidrug and toxin extrusion (MATE) transporters. MATE belongs to the SLC47 transporter family consisting of only two members, MATE1 and MATE2-K. MATE2-K is exclusively expressed in the kidney at the apical membrane of proximal tubular epithelial cells. MATE1 is highly expressed in the kidney, liver, skeletal muscle and also in adrenal glands, testes and heart. MATE1 exchanges organic cations against protons both in influx as well as in efflux modes.</p><p><strong>Methods: </strong>Here, we examined the interaction of 25 antineoplastic agents with human MATE1. We generated stably transfected MATE1-HEK293 cells and determined the inhibition of MATE1-mediated [(3)H]1-methyl-4-phenylpyridinium (MPP) uptake by the antineoplastic agents.</p><p><strong>Results: </strong>We found a significant inhibition of MATE1-mediated MPP uptake by several antineoplastic agents and pH dependent IC(50)values for mitoxantrone (7.8 μM at pH 7.4 and 0.6 μM at pH 8.5) as well as for irinotecan (4.4 μM at pH 7.4 and 1.1 μM at pH 8.5), respectively.</p><p><strong>Conclusions: </strong>We suggest that hMATE1 could play a role in chemosensitivity of tumor cells. In addition, hepatic and renal MATE1 could potentially be involved in drug-drug-interactions as well as in drug metabolism and excretion during chemotherapy.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"26 4","pages":"181-9"},"PeriodicalIF":0.0,"publicationDate":"2011-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/DMDI.2011.024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30308373","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}
Pub Date : 2011-01-01Epub Date: 2011-03-16DOI: 10.1515/DMDI.2011.104
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