Drug metabolism letters最新文献

{"title":"Quantification of Etodolac in Human Plasma for Pharmacokinetics and Bioequivalence Studies in 27 Korean Subjects.","authors":"Il-Dong Song, Ju‐Seop Kang, Hyunjin Kim, Semi Kim, Dongxue Zhao, Shin-Hee Kim, M. Chun, Kyu-Hyun Lee","doi":"10.2174/1872312811666170116151004","DOIUrl":"https://doi.org/10.2174/1872312811666170116151004","url":null,"abstract":"OBJECTIVE We developed a simple and validated liquid chromatography tandem mass spectrometry( LC-MS/MS) for quantification of etodolac using pioglitazone as an internal standard (IS) to assess pharmacokinetics and to appraise bioequivalence of two formulations of etodolac (reference and tested) in 27 healthy Korean subjects. METHODS Isocratic mobile phase consisted of 10 mM ammonium formate and acetonitrile were used to separate the analytes on a Gemini C18 column. Also, analytes were analyzed by MS/MS in multiple reaction monitoring (MRM) mode using the transitions of (M+H)+ ions, m/z 288.2→ 172.3 and m/z 357.1→ 134.2 for quantification of etodolac and IS each. The standard calibration curves displayed significant linearity within the range of 0.2-30.0 μ g/mL (r2=0.9956, 1/x2 weighting) with LLOQ of 0.1 μg/mL. RESULTS The retention times of etodolac and the IS were 0.77 min and 0.57 min each, indicating the high-throughput potential of the proposed method. The pharmacokinetic parameters were calculated from the plasma samples and data form the reference and test drugs were represented as follows; Area under plasma concentration-time curve (AUCt) (78.03 vs. 84.00 μgxh/mL), AUC∞ (86.67 vs. 93.92 μgxh/mL), maximal plasma concentration (Cmax) (19.49 vs. 18.94 μg/mL), time for maximal concentrations (Tmax) (2.13 vs. 2.26 h), Plasma elimination half-life (T1/2) (8.12 vs. 8.47 h), elimination rate constant (λz) (0.0853 vs. 0.0818 h-1). Pharmacokinetic parameters with 90% confidence interval fall within the bioequivalence range of 80-125%. CONCLUSION Thus, the new testified method was successfully applied for the pharmacokinetic and bioequivalence studies for two etodolac formulations.","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"10 4 1","pages":"286-294"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68049361","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":"Pharmacokinetics, Metabolism and Disposition of [14C]XQ-1H After Intravenous Administration to Male Rats.","authors":"Yin-lin Qin, Tao Chen, Qiu Jin, Kai Guo, Hao Feng, Dennis Heller, Zhe-ming Gu","doi":"10.2174/1872312811666170118162931","DOIUrl":"https://doi.org/10.2174/1872312811666170118162931","url":null,"abstract":"OBJECTIVE This study describes the in vivo pharmacokinetics and metabolism of [14C]labeled XQ-1H in male rats. METHODS XQ-1H is a methanesulfonate of XQ, 10-O-(N,N-dimethylaminoethyl)-ginkgolide B, a derivative of ginkgolide B (GB) with enhanced water solubility. Since it is very difficult to synthesize radiolabeled GB, the results obtained in this study may provide helpful insight to further ADME investigation of GB and its analogue compounds. After an i.v. administration of [14C]XQ-1H to male rats, XQ (the freebase form of XQ-1H) was extensively hydrolyzed, moderately metabolized, and mainly excreted in feces (71.5% of the dose) via the biliary route. RESULTS The main enzyme mediated metabolic pathways were mono- and di-demthylation. Using the radiolabel form of XQ-1H, the temporal binding of XQ to red blood cells was observed. CONCLUSION Binding of XQ to RBCs may lower the blood's viscosity and thus provide symptomatic improvement of ischemic stroke patients.","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"10 4 1","pages":"228-239"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68049372","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":"A Pharmacokinetic-Pharmacodynamic Model of Tamoxifen and Endoxifen to Predict Their Distribution and Effects on Inhibition of Tumor Growth.","authors":"Shengyue Yuan,&nbsp;Qingrong Sun,&nbsp;Yao Chen,&nbsp;Jun Liao","doi":"10.2174/1872312811666170815160751","DOIUrl":"https://doi.org/10.2174/1872312811666170815160751","url":null,"abstract":"<p><strong>Background: </strong>Tamoxifen is widely used in the therapy for breast cancer and has three major metabolites, N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen. Endoxifen has played a major role in the inhibition of tumor growth of breast cancer and the tumor growth is related to endoxifen concentration.</p><p><strong>Objectives: </strong>The aim of this study was to develop a pharmacokinetic-pharmacodynamic model to predict the distribution of tamoxifen and endoxifen quantitatively, and to discover the anti-tumor effect patterns of tamoxifen and endoxifen.</p><p><strong>Methods: </strong>The pharmacokinetic-pharmacodynamic model was established by integrating a four compartments pharmacokinetics model and a pharmacodynamic model, the first one include central compartment and peripheral compartment both of which contain tamoxifen and endoxifen. The parameters of the model were calculated by the values of plasma concentrations and the tumor growth data before and after the administration of tamoxifen.</p><p><strong>Results: </strong>The transport rate k42 (6.0003) of endoxifen from the peripheral compartment to the central compartment and the metabolism rate k34 (0.0031) from tamoxifen to endoxifen in the peripheral compartment were proven to be significant, which showed that tamoxifen and endoxifen are mainly distributed in the central compartment. The model provided reasonable predictions of tumor growth, which was inhibited after the administration and varies with the concentration of endoxifen.</p><p><strong>Conclusion: </strong>We established a PK-PD model of tamoxifen and endoxifen to predict the tumor growth. The parameters of the pharmacodynamic model, which characterized the tumor growth, revealed the patterns of tamoxifen's anti-tumor functions. The PK-PD model successfully provided illustration for the pharmacokinetics of tamoxifen and endoxifen, and predicted the inhibition effect of endoxifen on the tumor growth.</p>","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"11 2","pages":"93-101"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35275232","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":"Strong Induction of Cytochrome P450 1A/3A, But not P450 2B, in Cultured Hepatocytes from Common Marmosets and Cynomolgus Monkeys by Typical Human P450 Inducing Agents.","authors":"Shotaro Uehara, Y. Uno, Takako Suzuki, Takashi Inoue, M. Utoh, E. Sasaki, H. Yamazaki","doi":"10.2174/1872312810666161114144412","DOIUrl":"https://doi.org/10.2174/1872312810666161114144412","url":null,"abstract":"BACKGROUND Common marmosets (Callithrix jacchus) and cynomolgus monkeys (Macaca fascicularis) are used as non-human primate models in preclinical studies for drug development. OBJECTIVE The assessment of P450 induction in hepatocytes from marmosets and cynomolgus monkeys was performed using typical P450 inducers. METHODS Induction of cytochrome P450 1-4 family enzymes was analyzed in two lots of cultured hepatocytes from common marmosets and cynomolgus monkeys after 24-h treatment with typical human P450 inducing agents by real-time reverse transcription-polymerase chain reaction. RESULTS Marmoset P450 3A4 mRNA and P450 2C8/2C19 mRNA in hepatocytes were strongly (>10- fold) and weakly (>2) induced by rifampicin, respectively. Marmoset 1A1 and 1A2 mRNA were induced strongly (>200-fold) by β-naphthoflavone and omeprazole. Marmoset P450 2B6 mRNA was induced (~5-fold) by a constitutive androstane receptor agonist, but not by phenobarbital. Cynomolgus monkey P450 3A4 mRNA and P450 1A1 mRNA in cultured hepatocytes were also induced by rifampicin and omeprazole, respectively, but P450 2B6 mRNA was not induced by phenobarbital. CONCLUSION These results indicate that P450 1A/3A induction by typical human P450 inducers in hepatocytes from marmosets and/or cynomolgus monkeys are similar to those of humans (except for P450 2B induction by phenobarbital in humans), suggesting that marmosets and cynomolgus monkeys might be suitable models for evaluating the drug interactions in preclinical studies.","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"10 4 1","pages":"244-253"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68049753","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":"Ortho-Methylarylamines as Time-Dependent Inhibitors of Cytochrome P450 1A1 Enzyme.","authors":"Jayalakshmi Sridhar, Jiawang Liu, Rajesh Komati, Richard Schroeder, Quan Jiang, Phan Tram, Kevin Riley, Maryam Foroozesh","doi":"10.2174/1872312810666161220155226","DOIUrl":"10.2174/1872312810666161220155226","url":null,"abstract":"<p><strong>Background: </strong>Members of the cytochrome P450 1A family metabolize many procarcinogens such as polycyclicaromatic hydrocarbons and heterocyclic amines. Inactivation of these enzymes is a prerequisite for cancer prevention and treatment in certain cases. Mechanism-based inhibition (time and co-factor dependent) is an effective method for the inactivation of these enzymes. Our recent study on emodin analogs revealed an anthraquinone with ortho-methylarylamine moiety that exhibited timedependent inhibition of P450 enzymes 1A1 and 1A2.</p><p><strong>Methods: </strong>To determine whether the amino group or the methyl group or both were responsible for the time-dependent inhibition of these enzymes, a set of eleven compounds containing the orthomethylarylamine moiety were identified through a database search, and studied for the inhibition of the P450 enzymes 1A1, 1A2, 2A6 and 2B1. Our earlier studies on carbazole derivatives provided us with highly selective P450 1A2 inhibitors. Glycine scanning studies were performed on the docked proteinligand complexes of compounds 1-20 in order to understand the contribution of different protein residues towards the ligand binding.</p><p><strong>Results: </strong>Four compounds were found to cause selective time-dependent inhibition of P450 1A1 with KI values ranging from 0.24 to 8.25 mM. These compounds exhibited only direct inhibition of P450 1A2. Molecular modeling studies of these molecules indicated that the shapes of the molecules, their binding modes, and the methyl substituent in close proximity (4.5-5.7 Å) to the heme-Fe all contributed to their selective time-dependent inhibition activity on P450 1A1. Glycine scanning studies for P450 1A1 indicated that ligand interaction with Phe123 was the strongest binding contributor and similar studies for P450 1A2 indicated that ligand interactions with the phenylalanine residues 226 and 260 were the largest binding contributors.</p><p><strong>Conclusion: </strong>Four compounds have been identified that exhibit selective time-dependent inhibition of P450 1A1. Modeling studies have indicated that the proximity of the aromatic methyl group to the heme-Fe could be the main contributor for time-dependent inhibition. Future studies will focus on the confirmation of the involvement of the aromatic methyl group in enzyme inactivation.</p>","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"10 4 1","pages":"270-277"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68049814","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":"Analysis of Elevated Levels of Nandrolone Decanoate Induced Cytochrome- P450 Alterations in Mice.","authors":"Parmita Chowdhury,&nbsp;Rita Mahanta","doi":"10.2174/1872312811666171114145535","DOIUrl":"https://doi.org/10.2174/1872312811666171114145535","url":null,"abstract":"<p><strong>Background: </strong>Frequent recreational use of Anabolic Androgenic Steroids (AAS) is an instance of substance abuse which mimics the status of a natural hormone and upon prolonged exposure may lead to adverse drug reactions. These adverse drug reactions proceed in a manner so as to alter the normal metabolism of an enzyme mediated pathway such as the Cytochrome P450 (CYP) family of enzymes.</p><p><strong>Objective: </strong>The present study was conducted to investigate the impact of overuse of Nandrolone Decanoate (ND), an AAS, upon CYP enzyme activity and a CYP gene, belonging to CYP1 family.</p><p><strong>Methods: </strong>The study was carried out using normal and ND treated male albino mice. Genetic analysis was conducted using normalized and treated cDNA and reverse transcriptase polymerase chain reaction based assays. For enzyme assay, 0.1ml of 25 mg ND was administered to the animals twice a week for a period of 90 days. Genetic analysis was carried out with the same dose but administered for a period of 360 days.</p><p><strong>Results: </strong>CYP enzyme activity increased significantly (p<0.01) in the ND treated group of animals compared to that in the normal group. However, no noticeable alteration was observed at the molecular level.</p><p><strong>Conclusion: </strong>From the present study it could be inferred that, at elevated doses, ND has the potential to alter hepatic CYP enzyme activity without any modification in the CYP gene. This could be due to a possible adaptive response of the living system to such drugs.</p>","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"11 2","pages":"86-92"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35610102","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 Farnesoid X Receptor Target Gene Induction in Human Hepatocytes: Amino Acid Conjugation.","authors":"Jean Simmermacher,&nbsp;Michael Sinz","doi":"10.2174/1872312812666171227213946","DOIUrl":"https://doi.org/10.2174/1872312812666171227213946","url":null,"abstract":"<p><strong>Background: </strong>The nuclear hormone receptor, Farnesoid X Receptor (FXR) regulates the transcription of genes associated with bile acid metabolism and disposition.</p><p><strong>Objective: </strong>This study investigates possible changes in the expression of target genes responsible for amino acid conjugation, i.e., Bile Acid-CoA Synthetase (BACS) and bile acid-CoA: amino acid Nacetyltransferase (BAT). These genes have been shown to be inducible by FXR agonists in rat models, however, to date no studies have been conducted in a human hepatocyte model.</p><p><strong>Results: </strong>In human hepatocytes, treatment with the FXR agonists GW4064 (1.0 µM) and WAY362450 (0.1 µM) did not significantly induce the mRNA expression of BACS and BAT genes. However, other target genes associated with FXR activation, such as Bile Salt Export Pump (BSEP), Short Heterodimer Partner (SHP), Multidrug Resistance-associated Protein 2 (MRP2) and Multidrug Resistance Protein 3 (MDR3), were upregulated. Interestingly, a follow up study conducted in rat hepatocytes indicated that GW4064 induced the BACS gene while WAY362450 induced the BAT gene, confirming literature results that these genes can be induced in rat.</p><p><strong>Conclusion: </strong>In conclusion, there appears to be some species differences in the activation of FXR target genes.</p>","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"11 2","pages":"138-143"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35692504","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":"Therapeutic Potentials and Cytochrome P450-Mediated Interactions Involving Herbal Products Indicated for Diabetes Mellitus.","authors":"Cyprian O Onyeji,&nbsp;Sharon I Igbinoba,&nbsp;Gbola Olayiwola","doi":"10.2174/1872312811666171121104431","DOIUrl":"https://doi.org/10.2174/1872312811666171121104431","url":null,"abstract":"<p><strong>Background: </strong>There has been an increase in the use of herbal products to complement conventional drugs in the treatment of various diseases especially in developing countries. This may be attributable to the potential cost-effectiveness and ease of accessibility of these products as well as the perception of their safety profiles. However, there are numerous literature reports on herbs altering the pharmacokinetics and pharmacodynamics of other co-administered drugs thereby modulating the therapeutic outcomes. The prevalence of diabetes is on a steady increase worldwide and it is now identified as one of the main threats to human health.</p><p><strong>Objective: </strong>It is important that knowledge on specific effects of antidiabetic herbs and their products on drug metabolizing enzymes are updated and documented so as to ensure optimization of their therapeutic utility. This review, therefore, aims to highlight herbal products with evidence-based antidiabetic effects, identify their bioactive phyto-constituents, and also focus on the important Cytochrome P450 and consequences of their inhibition or induction.</p><p><strong>Methods: </strong>An extensive literature search was undertaken and the information obtained were critically analyzed and discussed.</p><p><strong>Results and conclusion: </strong>The literature abounds with reports on the utilization of herbal medications for the treatment of diabetes mellitus since time immemorial, but very few of these herbal products have undergone clinical trials. Also, studies on the herb-drug interactions were limited. Due to the complex phytochemical composition of the herbs, concomitant administration with conventional drugs resulted in alterations of pharmacological effects of some drugs. Evidences of beneficial interactions were identified for medical exploitation.</p>","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"11 2","pages":"74-85"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35629807","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":"A Novel Liquid Chromatography Tandem Mass Spectrometry Method for the Estimation of Bilirubin Glucuronides and its Application to In Vitro Enzyme Assays.","authors":"S. P. Putluru, M. Matta, Deepak Ahire, Murali Subramanian, M. Sinz, S. Mandlekar","doi":"10.2174/1872312810666161124143522","DOIUrl":"https://doi.org/10.2174/1872312810666161124143522","url":null,"abstract":"BACKGROUND Bilirubin is a toxic waste product of metabolism, eliminated mainly through UGT1A1 mediated conjugation to mono- and di-glucuronides. Due to the potentially low Km value of bilirubin glucuronidation, the quantitative sensitivity obtained with most UV/visible light detection methods are not sufficient to accurately calculate UGT1A1 enzyme kinetics at low bilirubin concentrations. In addition, bilirubin, as well as its metabolites, are unstable during sample preparation and bioanalysis. This necessitates the need for a rapid, sensitive and robust assay to measure bilirubin glucuronides. METHODS A robust LC-MS/MS method was developed to measure low levels of bilirubin glucuronides accurately from in vitro incubations, as well as stabilizing the analytes during sample preparation and analysis. The metabolites were quantified using a qualitative/quantitative approach utilizing UV to MS correction, thereby eliminating the need for synthetic standards. RESULTS The method was sensitive enough to quantify mono- and di-glucuronides as low as 3 nM from in vitro incubations, and kinetic data was determined for total glucuronide formation. The Km and Vmax values for total bilirubin glucuronide formations were determined to be 0.05 ± 0.01 μM and 181.9 ± 5.3 pmol/min/mg-protein, respectively, in human recombinant UGT1A1, and 0.23 ± 0.05 μM and 875 ± 45 pmol/min/mg protein in human liver microsomes (HLM). CONCLUSION We have developed a sensitive LC-MS/MS based method for the quantitation of bilirubin and its glucuronides from in vitro incubations. This method was successfully utilized to determine bilirubin glucuronidation kinetics in HLM and human rUGT1A1.","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"10 4 1","pages":"264-269"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68049799","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":"Genotoxicity of 4-(piperazin-1-yl)-8-(trifluoromethyl)pyrido[2,3-e][1,2,4] triazolo[4,3-a]pyrazine, a Potent H4 Receptor Antagonist for the Treatment of Allergy: Evidence of Glyoxal Intermediate Involvement.","authors":"Mithat Gunduz,&nbsp;Amanda L Cirello,&nbsp;Peter Klimko,&nbsp;Jennifer L Dumouchel,&nbsp;Upendra A Argikar","doi":"10.2174/1872312811666171106151730","DOIUrl":"https://doi.org/10.2174/1872312811666171106151730","url":null,"abstract":"<p><strong>Background: </strong>4-(piperazin-1-yl)-8-(trifluoromethyl)pyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (1) is a small-molecule which demonstrated a sub-nM inhibitory potency toward the histamine H4 receptor (H4R). However, it was found to be mutagenic in an in vitro Ames assay. Metabolic bioactivation of 1 could potentially arise from the piperazine moiety by forming reactive intermediates such as glyoxal, aldehyde-imine and/or iminium ion, which could all lead to genotoxicity. The aim of this study was to investigate bioactivation of 1 to determine the potential causes of the genotoxicity and mitigate liabilities in this scaffold.</p><p><strong>Methods: </strong>1 was investigated for its genotoxicity in phenobarbital and β-naphthoflavone induced Sprague Dawley rat liver S9 fractions. Trapping agents such as o-phenylenediamine was used postincubation.</p><p><strong>Results: </strong>Following metabolic profiling of 1, two oxidative metabolites were observed and identified in phenobarbital- and β -naphthoflavone induced Sprague Dawley rat liver S9 fractions. Metabolic pathway of 1 was primarily mediated by the metabolism of the piperazine moiety. The trapped glyoxal was identified by using high resolution LC-MS instrument. Structural characterization of the trapped glyoxal was determined by comparison of retention time, accurate mass measurement and Collision Induced Dissociation (CID) spectra to authentic standard.</p><p><strong>Conclusion: </strong>In the present investigation, a novel method was developed to trap glyoxal, which may potentially be liberated from piperazine moiety. These findings led to modifications on the piperazine ring to mitigate the bioactivation pathways leading to mutagenicity. Subsequently, the next generation compounds with modified piperazine moiety, retained H4R inhibitory potency in vitro and were not genotoxic in the Ames mutagenicity assay.</p>","PeriodicalId":11339,"journal":{"name":"Drug metabolism letters","volume":"11 2","pages":"144-148"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35582013","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}