Journal of Drug Metabolism and Toxicology最新文献

{"title":"Identification of Novel Metabolic Pathways of Sitagliptin (STG) by LC/MS and LC/MS2 after Incubations with Rat Hepatocytes","authors":"Osama I. G. Khreit, H. Grant, C. Henderson, D. Watson, Oliver B. Sutcliffe","doi":"10.4172/2157-7609.1000220","DOIUrl":"https://doi.org/10.4172/2157-7609.1000220","url":null,"abstract":"Sitagliptin (STG), a drug for treating Type Ii Diabetes Mellitus (T2DM), has been associated with severe joint pain in some patients. In this paper the metabolic profile of the drug has been investigated in order to determine metabolism and formation of reactive compounds which may contribute to this adverse effect. Metabolism of STG was investigated in vitro by incubation with freshly isolated Sprague-Dawley rat hepatocytes, to characterize Phase I and II metabolites, and the reaction mixture analysed on a zwitter ionic hydrophilic interaction (ZIC®-HILIC) column using LC-MS and LC-MS2 utilising electrospray ionization (ESI) in the positive ion mode. STG was metabolised to yield eleven metabolites, but in total only 3.1% of the parent drug was metabolised over 2 hrs incubation. These metabolites were structurally characterized on the basis of accurate mass analyses and the major metabolic routes for STG determined to be via aromatic oxidation (0.86%) and desaturation of N-C and C-C of the piperazine (0.44%). Novel metabolites of STG detected using these methods included STG N-glucuronide (M6) and a di-ketone metabolite (M4), hydroxylation of both the amine group and aromatic ring followed by formation of glucuronide metabolites (M5, M5’), oxidative desaturation of NH2 and di-hydroxylation of metabolites followed by loss of HF. Also, observed was an N-sulfate metabolite (0.07%) and acetylation followed by glucuronide conjugation was also found in trace amounts (<0.01%). MS2 fragment ions provide additional structural confirmation providing a possible structure for most metabolites such as by fragment ion loss of the glucuronide group (176 Da) from metabolite M5 and loss of the phenolic sulfate (80 Da) of N-Sulfate metabolite (M7). Reduction reaction of piperazine ring probably generates highly electrophilic metabolite of STG, which may be susceptible to produce adverse effects. Furthermore, N-oxidation reaction forming reactive intermediates metabolic to give a hydroxylamine metabolite that may undergo further reactions to yield electrophilic intermediate metabolites.","PeriodicalId":15537,"journal":{"name":"Journal of Drug Metabolism and Toxicology","volume":"24 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2016-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82384774","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":"Abnormal Retinal Structure and Function of Mother Wistar Rats Supplemented Aspartame, Glutamate and Galactose","authors":"H. El-Sayyad, Amora M Abou-El-Naga, Soad A. Khalifa, Eman A El-Shahari, Hamed A. N. Jala","doi":"10.4172/2157-7609.1000219","DOIUrl":"https://doi.org/10.4172/2157-7609.1000219","url":null,"abstract":"Three dietary supplements are investigated in the present study. Aspartame is a low calorie sweetener utilized \u0000 instead of sugar for diabetic patients. Monosodium Glutamate (MSG) is used in varieties of food stuffs to enhance \u0000 food flavor. Meanwhile galactose is presents in many of food items such as milk, dairy products, fruits and \u0000 vegetables and overloads enhanced aging like process and altered body function. The present work aimed to \u0000 illustrate the effect of dietary supplements of aspartame, glutamate and galactose in retina of mother Wistar rats. \u0000 Virgin Wistar rats were mated with fertile male and zero date of pregnancy was determined. Pregnant rats were \u0000 orally administered aspartame (100 mg/kg), monosodium glutamate (500 mg/kg) and galactose (1 g/kg body weight) \u0000 from 6th day of gestation until parturition and 21 days post-partum. Four main groups of pregnant rats were used; \u0000 control, aspartame, glutamate and galactose treatment. Each animal group was composed of ten individuals. Mother \u0000 rats were sacrificed at 21 days post-partum and their retinas were dissected and processed for histological, and \u0000 transmission electron microscopic investigation. Biochemical assessments of vascular endothelial growth factor \u0000 (VEGF), endothelin-1 (ET-1), adhesion molecules (ICAM-1 & VCAM-1), 8-hydroxy-deoxyguanosine (8-hdG), iron, \u0000 and zinc content were done. The present findings revealed that the used dietary supplements induced retinal \u0000 damage assessed by degeneration of ganglion cells, inner and outer nuclear layer and widespread necrotic patches \u0000 of photoreceptor outer segment. A striking missing of outer nuclear and photoreceptor outer segments was detected \u0000 post-glutamate treatment. Glutamate and galactose treatment showed apparent increase of pleomorphic and \u0000 pyknotic nuclei of inner and outer nuclear cells. The retinal thickness was markedly decreased in experimental \u0000 groups especially in those of glutamate treatment. Retinal serotonin, dopamine and zinc and iron contents were \u0000 markedly depleted, however, VEGF and ICAM-1& VCAM-1 and 8-hydroxy-guanosine were overexpressed in \u0000 experimentally-treated groups compared to the control. It can be concluded that the applied dietary supplements \u0000 affected the retinal structure and function of mother rats.","PeriodicalId":15537,"journal":{"name":"Journal of Drug Metabolism and Toxicology","volume":"83 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2016-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90531088","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":"The Frequency of UGT2B7*2 (802C>T) Allele among Healthy Unrelated Jordanian Volunteers","authors":"Y. Jarrar, F. Kherfan, A. Obaid, Lama A. Hamadneh, Al-Bawab Aq","doi":"10.4172/2157-7609.1000218","DOIUrl":"https://doi.org/10.4172/2157-7609.1000218","url":null,"abstract":"The UDP-Glucuronesyl Transferase (UGT) 2B7*2 802C>T is the most common functional genetic variant on UGT2B7 gene with reported influence on drug response. Objective: To determine the frequency of UGT2B7*2 (802C>T) genetic variant among Jordanian population. Methods: The DNA samples from 90 healthy Jordanian volunteers were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism assays (PCR-RFLP) to determine the UGT2B7*2 allele. Results: The frequency (95% confidence interval) of UGT2B7*2 802C allele was 0.59 (0.52 to 0.66) and for UGT2B7*2 802T was 0.41 (0.34 to 0.48), which was similar to the Caucasian but different than African ethnic populations. The UGT2B7 genotype frequency among Jordanians was 0.31 (0.22 to 0.4) for wild, 0.57(0.47 to 0.67) for heterozygote and 0.12 (0.06 to 0.18) for homozygote UGT2B7*2 genotype. Conclusion: This study reported for the first time the UGT2B7*2 frequency and genotype profile among Jordanians. The findings of this study will increase our understanding in explaining the inter-individual variation in drug response among Jordanian population.","PeriodicalId":15537,"journal":{"name":"Journal of Drug Metabolism and Toxicology","volume":"61 1","pages":"1-4"},"PeriodicalIF":0.0,"publicationDate":"2016-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73729145","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":"Effect of Molecular Structure, Substrate and Docking Scores on the Prediction of the Inhibition Constants of P-glycoprotein Inhibitors","authors":"M. Sharifi, Alexey V Raevsky, T. Ghafourian","doi":"10.4172/2157-7609.1000217","DOIUrl":"https://doi.org/10.4172/2157-7609.1000217","url":null,"abstract":"P-glycoprotein (P-gp) is a multispecific transporter which has a natural detoxification role. The inhibition of substrate transport by P-gp can be presented by a number of parameters, including percentage inhibition and IC50. Inhibition constant, Ki, is believed to be a more universal parameter allowing easy comparison of data from different substrate conditions. The aim of this investigation was to use molecular descriptors of the inhibitors, docking scores, and the parameters of the probe substrate for the development of Quantitative Structure-Activity Relationships (QSARs) for the prediction of P-gp inhibition constants. QSARs were developed using a number of data mining and pre-processing feature selection methods. A chi-square based regression tree followed by a boosted trees model were the most accurate in the estimation of Ki. The selected models incorporated molecular descriptors of the inhibitors followed by the molecular descriptors of probe substrates, whereas no docking scores were selected by the models. Potent P-gp inhibitors showed higher lipophilicity and molecular weights than those molecules defined by Oprea's rule.","PeriodicalId":15537,"journal":{"name":"Journal of Drug Metabolism and Toxicology","volume":"17 1","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2016-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87309164","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":"Protective Effect of Rosemary (Rosmarinus officinalis) Extract on Lithium-Induced Renal and Testis Toxicity in Albino Rats","authors":"M. Mwaheb, O. Sayed, Safaa H. Mohamed","doi":"10.4172/2157-7609.1000216","DOIUrl":"https://doi.org/10.4172/2157-7609.1000216","url":null,"abstract":"Lithium is used common as an effective drug for the medication of many psychiatric disorders in human. The current study was proceed to analysis the protective effect of rosemary leaves extract on renal and testis toxicity induced by Lithium in rats. Forty adult Albino male rats were divided into four equal groups. Group (I) was kept on standard rodent chow and served as healthy control group, Group (II) were orally administrated with 220 mg/kg/day of rosemary extraction, group (III) were orally administrated with 100 mg/kg/day of lithium carbonate (Li2CO3) and Group (IV) were orally administrated with both 220 mg/kg/day rosemary extraction and 100 mg/kg/day (Li2CO3). All groups were treated for 4 weeks. Lithium caused significant increase in plasma Malondialdehyde (MDA), creatinine, urea, Neuron Specific Enolase (NSE) and Human Chorionic Gonadotropin (HCG) levels, and while, significant decrease in plasma free and total testosterone, Superoxide Dismutase (SOD) and Glutathione (GSH) levels has been reported as compared to healthy control group. On the other side, treatment with rosemary extraction was significantly improving the level of oxidative stress, biomarkers (HCG), (NSE) and routine blood test of kidney function. Conclusion, rosemary leaves extract had a protective effect against renal and testis toxicity induced by lithium in rats.","PeriodicalId":15537,"journal":{"name":"Journal of Drug Metabolism and Toxicology","volume":"107 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2016-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74228738","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":"Transporter Role in Drug Efficacy and Organ Toxicity: Four Pillars ofClinical Trial Survival","authors":"Y. Lai","doi":"10.4172/2157-7609.1000E139","DOIUrl":"https://doi.org/10.4172/2157-7609.1000E139","url":null,"abstract":"Lack of efficacy and safety issues leading to an insufficient therapeutic index are the most common reasons of drug candidate attrition by drug development phase [1,2]. In order to overcome inadequate clinical efficacy, a number of fundamental elements, also known as three pillars of phase II survival, were summarized [3]. These pillars include 1) sufficient drug concentration at the target site of action over a desired period of time is confirmed; 2) a drug binds the pharmacological target; and 3) the target expressed pharmacological activities desired. Moreover, in order to optimize safety profiles for sufficient therapeutic index, minimizing drug exposure to off-target sites/organs has been set as the forth pillar of clinical trial survival [4].","PeriodicalId":15537,"journal":{"name":"Journal of Drug Metabolism and Toxicology","volume":"9 1","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2016-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86881235","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":"Human Pharmacokinetics Prediction","authors":"H. Asana","doi":"10.4172/2157-7609.1000E138","DOIUrl":"https://doi.org/10.4172/2157-7609.1000E138","url":null,"abstract":"Drug development is very time consuming and costly process. Only few candidates enters in to clinical trials can eventually become a drug. Accurate prediction of the right dose before entering in to clinical study can reduce time as well as cost of drug discovery process. Pharmacokinetic plays an essential role in the selecting the right dose and dosage regimen [1-5]. Thus early prediction of human pharmacokinetic based on animal and in-vitro data is the challenging task for the scientist. Predictions of human pharmacokinetic parameters include the clearance, volume of distribution, half-life, bioavailability, effective dose and dosage regimen, plasma concentration time profile; inter individual variability and drug-drug interaction. There are numerous methodologies available in the literature for human prediction. Most widely used methods are the Invitro In-vivo Extrapolation (IVIVE), allometric scaling and Physiologically Based Pharmacokinetic modeling (PBPK) [6-8]. Best results in the prediction can be obtained by applying one or two methods in a combination.","PeriodicalId":15537,"journal":{"name":"Journal of Drug Metabolism and Toxicology","volume":"3 1","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2016-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87840561","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":"Treatment of Depression in Patients on Anticoagulation Therapy:Antidepressant-Rivaroxaban Drug Interactions","authors":"C. Aguiar","doi":"10.4172/2157-7609.1000215","DOIUrl":"https://doi.org/10.4172/2157-7609.1000215","url":null,"abstract":"The use of Oral Anticoagulants (OAC) is recommended for stroke prevention. Rivaroxaban is a new generation oral anticoagulant. Depression and anxiety are psychiatric disorders which frequently coexist with the Coronary Artery Disease (CAD) and other cardiovascular diseases. In the last decades, there has been an increase in the use of antidepressants. This literature review aims to provide a general view of pharmacokinetic knowledge of drug interactions between rivaroxaban and antidepressants. Since rivaroxaban is metabolized by CYP3A4, the use of antidepressants that are inhibitors of this isoenzyme, such as fluoxetine, sertraline, paroxetine and fluvoxamine must be avoided. Based on drug interactions in cytochrome p450, it has been concluded that the use of escitalopram, citalopram, venlafaxine, mirtazapine or milnacipran would be safer in these patients since these drugs have a minimum CYP 450 inhibition potential.","PeriodicalId":15537,"journal":{"name":"Journal of Drug Metabolism and Toxicology","volume":"30 1","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2016-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77444114","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":"Editorial: Accurate Mass Measurements in Identification of Metabolites","authors":"B. Raju, K. P. Kim","doi":"10.4172/2157-7609.1000E137","DOIUrl":"https://doi.org/10.4172/2157-7609.1000E137","url":null,"abstract":"Identification of metabolites is an important aspect in the drug discovery and development process [1,2]. For better understanding the drug efficiency and safety profiles, it is essential to study the drug metabolism in animals or humans and to identify the reactive and toxic metabolites [3,4]. The information generated in the identification of metabolites can be used to identify lead compounds and adverse metabolic products followed by optimization of pharmacokinetic and safety profiles. Identification of metabolites is usually carried out in in vitro and in vivo models and liquid chromatography-mass spectrometry (LC-MS) [5-9] is a powerful technique that can use in identification of metabolites. In particular, Q-TOF can be efficiently used to perform LC/MS and MS/MS experiments with better resolution and good mass accuracy for both molecular and fragment ions [6-9]. Accurate mass data of the metabolites that were acquired on a Q-TOF-MS provides additional supporting information on their identification. The predicted formulas observed and calculated masses (m/z value) and mass errors (ppm) help in structural characterization of each unknown metabolite. The application of accurate mass measurements (HRMS data with error in ppm) is very important in identification of metabolites for distinguishing isobaric molecular ions and assigning fragment ions to elucidate the fragmentation mechanisms [8]. Knowing the accurate mass can confirm the molecular formula of the entity under investigation. Further, the trace level metabolites can also be verified by extracting the accurate masses of metabolites to confirm their elemental compositions in structure elucidation. Accurate masses of the elemental compositions of metabolites and their fragment ions that are confirmed by HRMS are within ±5 ppm of calculated exact masses. Interpretation of the product ion spectra obtained from Q-TOF may help to confirm the structure of each fragment ion [6-9]. The structure elucidation of metabolites can be effectively achieved with the help of HR-MS/MS spectra when compared to MS/MS spectra obtained from low resolution instruments. Thus, with help of accurate mass measurements performed on Q-TOF, unambiguous metabolite identification [6-9], which can be very useful in the early stages of drug discovery, can be achieved without the use of large scale preparation for NMR or other analytical characterizations.","PeriodicalId":15537,"journal":{"name":"Journal of Drug Metabolism and Toxicology","volume":"4 1","pages":"1-1"},"PeriodicalIF":0.0,"publicationDate":"2016-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81842048","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":"Scarlet Fever in Human: A Brief Overview","authors":"S. Ganguly, R. Wakchaure","doi":"10.4172/2157-7609.1000E136","DOIUrl":"https://doi.org/10.4172/2157-7609.1000E136","url":null,"abstract":"Scarlet fever is a disease occurring in human beings due to group A Streptococcus (group A strep) infection. The signs and symptoms include a fever, sore throat, lymphadenopathy, sore throat and a characteristic rash. Children between 5 to 15 years age are most susceptible to this infection.","PeriodicalId":15537,"journal":{"name":"Journal of Drug Metabolism and Toxicology","volume":"6 1","pages":"1-1"},"PeriodicalIF":0.0,"publicationDate":"2016-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82532419","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}