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81.
ABSTRACT

Metabolite identification is an essential part of the drug discovery and development process. Experimental methods allow identifying metabolites and estimating their relative amount, but they require cost-intensive and time-consuming techniques. Computational methods for metabolite prediction are devoid of these shortcomings and may be applied at the early stage of drug discovery. In this study, we investigated the possibility of creating SAR models for the prediction of the qualitative metabolite yield (‘major’, ‘minor’, ”trace” and ”negligible”) depending on species and biological experimental systems. In addition, we have created models for prediction of xenobiotic excretion depending on its administration route for different species. The prediction is based on an algorithm of naïve Bayes classifier implemented in PASS software. The average accuracy of prediction was 0.91 for qualitative metabolite yield prediction and 0.89 for prediction of xenobiotic excretion. The created models were included as a component of MetaTox web application, which allows predicting the xenobiotic metabolism pathways (http://www.way2drug.com/mg).  相似文献   
82.
In vitro metabolic stability experiments using microsomes or other liver preparations are important components in the discovery and lead-optimization stages of compound selection in the pharmaceutical industry. Currently, liquid chromatography-tandem mass spectrometric (LC-MS/MS) support of in vitro metabolic stability studies primarily involves the monitoring of disappearance of parent compounds, using selected reaction monitoring (SRM) on triple-quadrupole instruments. If moderate to high turnover is observed, separate metabolite identification experiments are then conducted to characterize the biotransformation products. In this paper, we present a novel method to simultaneously perform metabolite screening in addition to the quantitative stability measurements, both within the same chromatographic run. This is accomplished by combining SRM and SRM-triggered, information-dependent acquisition (IDA) of MS/MS spectra on a hybrid triple-quadrupole linear ion trap (QqQLIT) mass spectrometer. Microsomal stability experiments using model compounds, bufuralol, propranolol, imipramine, midazolam, verapamil and diclofenac, were used to demonstrate the applicability of our approach. This SRM + SRM-IDA approach generated metabolic stability results similar to those obtained by conventional SRM-only approach. In addition, MS/MS spectra from potential metabolites were obtained with the enhanced product ion (EPI) scan function of LIT during the same injection. These spectra were correlated to the spectra of parent compounds to confirm the postulated structures. The time-concentration profiles of identified metabolites were also estimated from the acquired data. This approach has been successfully used to support discovery programs.  相似文献   
83.
A fully valid UHPLC–MS/MS method was developed for the determination of etoposide, gemcitabine, vinorelbine and their metabolites (etoposide catechol, 2′,2′‐difluorodeoxyuridine and 4‐O ‐deacetylvinorelbine) in human plasma. The multiple reaction monitoring mode was performed with an electrospray ionization interface operating in both the positive and negative ion modes per compound. The method required only 100 μL plasma with a one‐step simple de‐proteinization procedure, and a short run time of 7.5 min per sample. A Waters ACQUITY UPLC HSS T3 column (2.1 × 100 mm, 1.8 μm) provided chromatographic separation of analytes using a binary mobile phase gradient (A, 0.1% formic acid in acetonitrile, v /v; B, 0.1% formic acid in water, v /v). Linear coefficients of correlation were >0.995 for all analytes. The relative deviation of this method was <10% for intra‐ and inter‐day assays and the accuracy ranged between 86.35% and 113.44%. The mean extraction recovery and matrix effect of all the analytes were 62.07–105.46% and 93.67–105.87%, respectively. This method was successfully applied to clinical samples from patients with lung cancer.  相似文献   
84.
Drug metabolism studies are performed in drug discovery to identify metabolic soft spots, detect potentially toxic or reactive metabolites and provide an early insight into potential species differences. The relative peak area approach is often used to semi‐quantitatively estimate the abundance of metabolites. Differences in the liquid chromatography‐mass spectrometry responses result in an underestimation or overestimation of the metabolite and misinterpretation of results. The relative MS response factors (RF) of 132 structurally diverse drug candidates and their 233 corresponding metabolites were evaluated using a capillary‐liquid chromatography/high‐resolution mass spectrometry system. All of the synthesized metabolites discussed here were previously identified as key biotransformation products in discovery investigations or predicted to be formed. The most commonly occurring biotransformation mechanisms such as oxygenation, dealkylation and amide cleavage are represented within this dataset. However, relatively few phase II metabolites were evaluated because of the limited availability of authentic standards. Approximately 85% of these metabolites had a relative RF in the range between 0.2 (fivefold under‐prediction) and 2.0 (twofold over‐prediction), and the median MS RF was 0.6. Exceptions to this included very small metabolites that were hardly detectable. Additional experiments performed to understand the impact of the MS platform, flow rate and concentration suggested that these parameters do not have a significant impact on the RF of the compounds tested. This indicates that the use of relative peak areas to semi‐quantitatively estimate the abundance of metabolites is justified in the drug discovery setting in order to guide medicinal chemistry efforts. Copyright © 2017 John Wiley & Sons, Ltd.  相似文献   
85.
86.
A simple LC–tandem mass spectrometry (MS/MS) method to determine ebastine and carebastine (active metabolite) in human plasma was developed and validated. Analytes and internal standards were precipitated by protein precipitation and separated on Synergi Hydro-RP 80A column (4 μm, 50 mm × 2.0 mm; Phenomenex) by gradient elution with mobile phase A comprising 0.1% formic acid in 5 mm ammonium acetate (NH4Ac) and B comprising 100% methanol at a flow rate 0.4 mL/min. Ions were detected in positive multiple reaction monitoring mode, and they exhibited linearity over concentration range 0.01–8.0 and 1.00–300 ng/mL for ebastine and carebastine, respectively. A clinical pharmacokinetic study was conducted in healthy Chinese volunteers under fasting and fed conditions after a single oral administration of 10 mg ebastine. The maximum plasma concentration (Cmax), time to Cmax (Tmax) and elimination half-life for ebastine were 0.679 ± 0.762 ng/mL, 1.67 ± 1.43 h and 7.86 ± 6.18 h, respectively, whereas these for carebastine were 143 ± 68.4 ng/mL, 5.00 ± 2.00 h and 17.4 ± 4.97 h, respectively under fasting conditions; the corresponding values under fed conditions were 4.13 ± 2.53 ng/mL, 3.18 ± 1.09 h and 21.6 ± 7.77 h for ebastine and 176 ± 68.4 ng/mL, 6.14 ± 2.0 h and 20.0 ± 4.97 h for carebastine.  相似文献   
87.
3,4-Dicaffeoylquinic acid (3,4-DiCQA) is a dicaffeoylquinic acid that possesses antioxidant, anti-inflammatory, antibacterial, antiviral, anticancer, hypoglycemic, hypotensive, and hepatoprotective activities. This study developed a rapid and reliable method using ultra-high performance liquid chromatography equipped with linear ion trap-Orbitrap MS to identify the metabolites of 3,4-DiCQA in rat plasma, urine, feces, and tissues. The metabolic profile of 3,4-DiCQA was determined after an oral administration of 200 mg/kg to rats. A strategy of full scan-parent ions list acquisition coupled to diagnostic product ion analysis for screening and identification of target metabolites was used. A total of 67 metabolites, combined with accurate mass measurement, diagnostic ions, neutral losses, and reference standards, were observed and characterized for the first time. The results indicated that hydrolysis, methylation, hydrogenation, hydration, dehydroxylation, dehydrogenation, sulfate conjugation, and glucuronide conjugation were the major metabolic reactions of 3,4-DiCQA in vivo.  相似文献   
88.
The metabolism of swertiamarin (STM) in vivo was studied by LC/MS following picolinoyl derivatization. Incubation of erythrocentaurin (ECR), one of the main in vitro metabolites of STM by intestinal bacteria, with liver microsome indicated that STM may be metabolized to the final metabolite 3,4‐dihydro‐5‐(hydroxymethyl) isochroman‐1‐one (HMIO) in vivo. After hydrolyzation with sulfatase, HMIO was successfully detected in rat plasma after oral administration of STM by LC/MS following picolinoyl derivatization. 4‐Methoxyphenyl methanol was used as the internal standard to quantify HMIO in rat plasma. The full metabolic pathway of STM in rats is proposed. STM is first hydrolyzed by bacterial β‐glucusidase to give aglycone, which is readily converted to ECR and nitrogen‐containing metabolite. ECR is further reduced to HMIO by both liver and intestinal bacteria and HMIO is finally converted to the new sulfate conjugate metabolite. The monoterpene compound STM was found to be metabolized to dihydroisocoumarin and alkaloid compounds in vivo, which may be responsible for the pharmacological effect of STM. The results may shed light on clinical efficacy of STM and the new analytical method developed may assist in studies of the metabolism of other natural iridoids and secoiridoids in vivo. Copyright © 2013 John Wiley & Sons, Ltd.  相似文献   
89.
《Analytical letters》2012,45(10):2323-2334
Abstract

The title compound (TXB2?M) is a quantitative index of thromboxane A2 synthesis in the human. We developed a method for its determination in urine based on the use of the 13C-labeled methyl ester derivative of the analyte as internal standard and GC-EIMS. the interassay coefficient of variation (CV) was 5.3% (N=4) and the intraassay CV ranged from 2.6 to 8.2% (N=3). the equation of the regression curve correlating the amounts added and recovered was Y=0.932X+3.99 (R=0.9947). the relative recovery of TXB2?M from nine urine specimens was 99.8 ± 2.8% (mean ± SEM). the mean (±SD) 24-hr output in six healthy male subjects was 1371 ± 307 ng, and in six females it was 1176 ± 418 ng. Concentrations as low as 200 pg/ml of urine can easily be measured with this procedure if one uses 50 ml of urine for the analysis.  相似文献   
90.
Zhi‐zi‐chi decoction (ZZCD) is a classical formula widely used in Chinese clinical application. In the present study, a novel and efficient strategy has been developed for screening and identification of multiple constituents and their metabolites of ZZCD using ultra‐high‐performance liquid chromatography combined with triple time‐of‐flight mass spectrometry. The novel approach of an online data acquisition method dependent on multiple mass defect filter and dynamic background subtraction is combined with multiple data processing techniques. First, a total of 109 potential bioactive compounds were detected in ZZCD. Based on the same instrumental conditions, 100 compounds were found in rat biofluids after oral administration of ZZCD, including 61 original compounds of ZZCD as well as 39 metabolites. Conjugations with sulfate, glucuronate and amino acids were found as the predominant metabolic reaction of ZZCD. As more xenobiotics were detected in urine than those in bile were, it demonstrated that multiple components of ZZCD have undergone comprehensive renal excretion. This study reported the urinary and biliary excretion in rats after oral administration of ZZCD for the first time. The present study expands our knowledge about the constituents and metabolism of ZZCD, which could be very useful for further pharmacological and clinical studies of ZZCD.  相似文献   
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