Drug Metabolism and Drug Interactions最新文献

{"title":"Silibinin hemisuccinate binding to proteins in plasma and blood cell/plasma partitioning in mouse, rat, dog and man in vitro.","authors":"Stefano Persiani,&nbsp;Federica Sala,&nbsp;Richard Cole,&nbsp;Guy Webber,&nbsp;Gianfranco Caselli,&nbsp;Paola Vaghi,&nbsp;Lucio C Rovati","doi":"10.1515/dmdi-2013-0013","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0013","url":null,"abstract":"<p><strong>Background: </strong>The determination of plasma protein binding and blood cell/plasma partitioning is important when prescribing silibinin hemisuccinate to patients concomitantly receiving other drugs and to estimate the safety margins of exposure at the no observed adverse events levels determined from toxicity studies conducted in rats and dogs.</p><p><strong>Methods: </strong>Protein binding of [3'-14C]silibinin hemisuccinate (1, 10, 100, 1000 and 4000 μM) was evaluated in human, dog, rat and mouse plasma by ultrafiltration. Blood cell/plasma partitioning in all these species was also determined.</p><p><strong>Results: </strong>Silibinin hemisuccinate is highly bound to plasma proteins with percentage binding ranging from 94.3% to 97.8%. Its association with blood cells was negligible (<7%) in all species. The degree of protein binding was concentration independent up to the pharmacologically effective concentration of 100 μM. The blood cell/plasma partitioning indicates that distribution into blood cells is not an important feature for the disposition of silibinin hemisuccinate.</p><p><strong>Conclusions: </strong>No corrections for fraction unbound are needed when comparing human and preclinical pharmacokinetic and pharmacodynamic data at pharmacological doses, and it is appropriate to analyze plasma as opposed to whole blood for the determination of silibinin hemisuccinate concentrations.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 2","pages":"115-22"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31379988","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":"Caffeic acid inhibits organic anion transporters OAT1 and OAT3 in rat kidney.","authors":"Yuichi Uwai,&nbsp;Tatsuya Kawasaki,&nbsp;Tomohiro Nabekura","doi":"10.1515/dmdi-2013-0050","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0050","url":null,"abstract":"<p><strong>Background: </strong>Some food components influence drug elimination. Previously, we found that caffeic acid, present in coffee, fruits, and vegetables, strongly inhibited human homologs of organic anion transporters (OATs) OAT1 and OAT3, which are responsible for renal tubular secretion of anionic drugs. In this study, we examined the effect of caffeic acid on drug transport by OAT1 and OAT3 in the rat kidney.</p><p><strong>Methods: </strong>The inhibitory effect of caffeic acid on rat OAT1 and OAT3 was assessed by drug uptake experiment using Xenopus laevis oocytes. Urinary excretion of phenolsulfonphthalein (PSP), a diagnostic agent secreted by renal OATs, was examined in rats, and the influence of caffeic acid was evaluated.</p><p><strong>Results: </strong>Expression of rat OAT1 (rOAT1) and rOAT3 stimulated uptake of their typical substrates, p-aminohippurate and estrone sulfate, respectively, into oocytes, and caffeic acid inhibited them dose dependently. After intravenous injection of PSP in rats, 42.7% of the dose was excreted into urine up to 60 min, and the simultaneous administration of caffeic acid reduced it to 32.0%.</p><p><strong>Conclusions: </strong>These findings show that caffeic acid inhibits OAT1 and OAT3 in the rat kidney.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":" ","pages":"247-50"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40273131","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":"Clinical pharmacology of drug metabolism and drug interactions: clinical, interethnical and regulatory aspects.","authors":"Adrián Llerena","doi":"10.1515/dmdi-2013-0010","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0010","url":null,"abstract":"","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 1","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31272250","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":"Viewing drug action as network perturbation in multiple scale systems.","authors":"Robert Barouki","doi":"10.1515/dmdi-2013-0025","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0025","url":null,"abstract":"The biochemist view of drug action and chemical toxicity has traditionally focused on a single objective: find the target. This has indeed led to major discoveries in the field. However, we now know that target identification is not sufficient to predict the clinical fate of a drug. Chemical toxicity has also focused on identifying targets, but quickly enough biological pathways have also been considered. For example, in addition to the discovery of the dioxin target, the arylhydrocarbon receptor, scientists have identified the AhR gene battery, i.e., the collection of genes that were induced following the activation of this receptor. With the advent of omics technologies, we now know that many other genes are affected and that more than one pathway is altered [ 1 ]. A similar development has occurred with other targets of xenobiotics, notably the xenobiotic receptors PXR and CAR as described in this issue by Molnár et al. [ 2 ]. Systems biology has changed considerably our understanding of cell function in the last few years. Our view of a cell with more or less autonomous biological pathways has now to be reconsidered. The integration of large scale observations has lead to a new picture in which genes and proteins sharing functional or structural interactions are organized in networks. This is best illustrated by protein interactome studies which identified network of proteins based on physical interactions [ 3 ]. Similarly, gene expression studies have identified groups of genes sharing similar regulations. Integration of all those studies yields a complex picture of interaction between cellular components, indicating that different pathways may interact with each other in a time-dependent manner. This may help explain why modulating one pathway leads to much wider effects than expected and why cross-talks between pathways are readily observed. It is now believed that disease states are associated with cellular network alterations and that a genetic variation can disrupt these networks [ 4 ]. Drug effect and toxicity could also be viewed as resulting from the perturbation of cellular networks (as illustrated by Galizzi et al in this issue [ 5 ]). The advantage of such an approach is that not only the biological pathway directly connected to the drug target is considered, but also other pathways within the network. If a drug represses a protein, consequences are expected not only for those proteins immediately interacting with it, but also for more distal proteins through indirect interactions. As an example, if one considers the mechanisms of breast cancer resistance to tamoxifen chemotherapy, studies should not only focus on the estrogen receptor pathway but also on connected pathways involved in cellular proliferation and apoptosis, in addition to drug metabolism pathways [ 6 ]. Many other illustrations of perturbation of networks arise from pharmaco-metabolomics and pharmacogenomics studies. The concept of drugs acting by perturbing normal","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 2","pages":"65-6"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31578132","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":"MDR-1 genotypes and quetiapine pharmacokinetics in healthy volunteers.","authors":"Nicolás González-Vacarezza,&nbsp;Pedro Dorado,&nbsp;Eva M Peñas-Lledó,&nbsp;Humberto Fariñas,&nbsp;Francisco E Estévez-Carrizo,&nbsp;Adrián Llerena","doi":"10.1515/dmdi-2013-0008","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0008","url":null,"abstract":"<p><strong>Background: </strong>P-glycoprotein is an efflux transporter encoded by the multidrug-resistance MDR-1 gene, which influences the absorption and excretion of a variety of drugs. The relation between quetiapine pharmacokinetics and MDR-1 genetic polymorphisms remains controversial. Therefore, the aim of the present study was to analyze the association between quetiapine plasma concentrations and MDR-1 genetic polymorphisms in a bioequivalence trial.</p><p><strong>Methods: </strong>Quetiapine bioequivalence was studied in 24 unrelated healthy Caucasian adults with an open-label, randomized, cross-over, two-sequence and two-period design. Subjects were genotyped for 3435C>T and 1236C>T single-nucleotide polymorphisms. A linear mixed model was performed to compare pharmacokinetic parameters.</p><p><strong>Results: </strong>Subjects with 3435T/T genotype vs. C carriers showed a higher area under the concentration-time curve from 0 to 36 h (p=0.01). Subjects classified according to 1236C>T SNP and haplotypes showed no statistically significant differences.</p><p><strong>Conclusions: </strong>These results suggest that the polymorphic MDR-1, in particular the 3435C>T allelic variant, might influence plasma levels of quetiapine.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 3","pages":"163-6"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31576704","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":"Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6.","authors":"Sebastian Haertter","doi":"10.1515/dmdi-2013-0032","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0032","url":null,"abstract":"<p><p>The cytochrome P450 2D6 (CYP2D6) belongs to a group of CYPs considered of utmost importance in the metabolism of xenobiotics. Despite being of only minor abundance in the liver, it is involved in the clearance of >25% of marketed drugs. Accordingly, CYP2D6 can be very efficiently inhibited by a couple of commonly used drugs such as some antidepressants, although induction by any drug has not been observed thus far. CYP2D6 was also one of the first enzymes for which a highly polymorphic expression could be shown leading to a widespread range of functionality, from a complete lack of a functional enzyme to overexpression due to multiplication of active alleles. A clear relationship between the CYP2D6 genotype and adverse events during treatment with CNS-active drugs such as codeine, antidepressants, or antipsychotics could be demonstrated. More recently, some new aspects emerged about the potential endogenous function of CYP2D6 in terms of behavior and brain disorders.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 4","pages":"209-16"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31777604","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":"Regulatory polymorphisms in CYP2C19 affecting hepatic expression.","authors":"Jonathan C Sanford,&nbsp;Yingying Guo,&nbsp;Wolfgang Sadee,&nbsp;Danxin Wang","doi":"10.1515/dmdi-2012-0038","DOIUrl":"https://doi.org/10.1515/dmdi-2012-0038","url":null,"abstract":"<p><strong>Background: </strong>Cytochrome P450 2C19 is responsible for the metabolism of many drugs, including the activation of clopidogrel. The allele CYP2C19*17 is associated with ultra-rapid metabolizer phenotypes by increasing gene transcription. This study tests to what extent CYP2C19*17 enhances CYP2C19 expression in human liver and whether additional regulatory variants contribute to variation in CYP2C19 expression.</p><p><strong>Methods: </strong>CYP2C19 mRNA was measured with quantitative real-time PCR (qRT-PCR), enzyme activity as metabolic velocity with S-mephenytoin as the substrate and allelic mRNA expression ratio with SNaPshot in human livers. CYP2C19 transcribed exons and a 4kb promoter region were sequenced using IonTorrent PGM or Sanger sequencing and screened for polymorphisms associated with total hepatic CYP2C19 mRNA, enzyme activity and allelic mRNA ratios.</p><p><strong>Results: </strong>Livers heterozygote and homozygous for CYP2C19*17 had mRNA levels 1.8-fold (p=0.028) and 2.9-fold (p=0.006), respectively, above homozygous reference allele livers. CYP2C19*17 heterozygotes were also associated with increased allelic mRNA expression (allelic ratio ~1.8-fold, SD±0.6, p<0.005), whereas CYP2C19 enzyme activity was elevated 2.3-fold, with borderline significance (p=0.06) in CYP2C19*17 carriers. One liver sample of African ancestry displayed a 2-fold allelic expression ratio, and another sample, a ~12-fold increase in metabolic velocity. Neither case was accounted for by *17, which indicates the presence of additional regulatory variants.</p><p><strong>Conclusions: </strong>Our findings confirm *17 as a regulatory polymorphism enhancing hepatic CYP2C19 expression 2-fold with potential to compensate for the loss of function allele CYP2C19*2. Additional regulatory factors may also enhance CYP2C19 expression in African American populations.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 1","pages":"23-30"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2012-0038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31241216","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}

{"title":"Lexical fields of predictive and personalized medicine.","authors":"Thierry Mathieu,&nbsp;Laurent Bermont,&nbsp;Jean-Christophe Boyer,&nbsp;Céline Versuyft,&nbsp;Alexandre Evrard,&nbsp;Isabelle Cuvelier,&nbsp;Remy Couderc,&nbsp;Katell Peoc'h","doi":"10.1515/dmdi-2013-0024","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0024","url":null,"abstract":"<p><p>With human genome mapping, the omics revolution and the empowering sequencing technologies developed at the turn of the century, the new goals in medicine are to switch from population medicine to individualized therapies, not only to cure diseases but also to prevent them. The purpose of this review by the pharmacogenetics and predictive medicine working group of the French clinical biology society (SFBC) is to situate in their correct context the notions of personalized medicine, pharmacogenetics, genetics and genomics, emphasizing their interactions and discussing their significance for researchers and clinicians.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 2","pages":"125-32"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31578133","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":"Evaluation of drug-metabolizing enzyme hydroxylation phenotypes in Hispanic populations: the CEIBA cocktail.","authors":"Fernando de Andrés,&nbsp;Martha Sosa-Macías,&nbsp;Blanca P Lazalde-Ramos,&nbsp;María Eugenia G Naranjo,&nbsp;Eduardo Tarazona-Santos,&nbsp;Adrián Llerena","doi":"10.1515/dmdi-2013-0020","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0020","url":null,"abstract":"<p><p>Interindividual differences in response to drug treatments are mainly caused by differences in drug metabolism, in which cytochrome P450 (CYP450) enzymes are involved. Genetic polymorphisms of these enzymes have a key role in this variability. However, environmental factors, endogenous metabolism and disease states also have a great influence on the actual drug metabolism rate (metabolic phenotype). Consequently, the genotype does not always correlate with the actual drug hydroxylation phenotype. In this sense, in vivo phenotyping strategies represent an alternative to evaluate the interindividual variability in drug metabolism. Therefore, the 'cocktail' approach is considered as an advantageous strategy to obtain actual and reliable information on several CYP activities in just one experiment. As reviewed, phenotyping studies on Latin-American populations, which comprise about 400 million people, are scarce, and only selective phenotyping methods were applied. Therefore, a novel cocktail approach is here proposed as a phenotyping tool to evaluate the relationship between genotype and phenotype of major CYP enzymes in Hispanic populations. This determination will allow adaptation of drug therapies to these populations and consequently to benefit from the application of pharmacogenetics in the reduction of drug adverse effects and in the improvement of therapeutic responses.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":"28 3","pages":"135-46"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31614616","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":"Unexpected interaction between CYP3A4 and BI 11634: is BI 11634 interacting with CYP3A4 similar to nifedipine?","authors":"Arti Mathur,&nbsp;Donald J Tweedie,&nbsp;Holly Hlaing-Hlaing Maw,&nbsp;Yongmei Li","doi":"10.1515/dmdi-2013-0044","DOIUrl":"https://doi.org/10.1515/dmdi-2013-0044","url":null,"abstract":"<p><strong>Background: </strong>Interactions between cytochrome P450 3A4 (CYP3A4) and its substrates are complex with multiple binding sites within the active site. BI 11634 is a factor Xa inhibitor in drug development and its interaction with CYP3A4 was evaluated.</p><p><strong>Methods: </strong>Reaction phenotyping studies were conducted to determine human isoform(s) of cytochrome P450 responsible for BI 11634 metabolism using recombinant CYPs and specific chemical inhibitors. Metabolite identification and quantitation were performed for incubations of [14C]BI 11634 with human liver microsomes (HLMs) or recombinant CYP3A4 (rCYP3A4) using a high-performance liquid chromatography-mass spectrometry-radiomatic detector. Inhibition of the CYP3A4-mediated metabolism of BI 11634 by quinidine was further evaluated.</p><p><strong>Results: </strong>From the reaction phenotyping studies, it was shown that the metabolism of BI 11634 in HLM was inhibited by ketoconazole and quinidine, well-accepted specific inhibitors of CYP3A4 and CYP2D6, respectively. In contrast, BI 11634 metabolism was exclusively mediated by rCYP3A4. Additional studies confirmed that BI 11634 was metabolized by CYP3A4 to form one major metabolite and this reaction was inhibited by quinidine with a Ki of 7 µM.</p><p><strong>Conclusions: </strong>These data indicated that BI 11634 may interact with CYP3A4 similar to nifedipine. CYP3A4 substrates have been categorized into three subgroups, including a stand-alone subgroup for dihydropyridine calcium channel blockers such as nifedipine and felodipine. In addition, this study emphasizes the importance of using rCYP in conjunction with approaches relying on inhibition when conducting CYP450 reaction phenotyping studies, as one single method may generate misleading results. The specificity of quinidine as a CYP2D6 inhibitor is questionable as it can also significantly inhibit CYP3A4-mediated metabolism of some compounds.</p>","PeriodicalId":11319,"journal":{"name":"Drug Metabolism and Drug Interactions","volume":" ","pages":"239-46"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/dmdi-2013-0044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40273132","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}