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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/28316274/co-treatment-with-indole-3-carbinol-and-resveratrol-modify-porcine-cyp1a-and-cyp3a-activities-and-expression
#1
Galia Zamaratskaia, Rebekka Thøgersen, Marjeta Čandek-Potokar, Martin Krøyer Rasmussen
1. Humans and animals are commonly exposed to indole-3-carbinol (I3C) and resveratrol (RES) via food or beverages. Moreover, these compounds have been demonstrated to potentially cause food-drug interactions. However, information about their combined effects is limited. Therefore, we investigated the effects of I3C and RES, both as single compounds and in combination, on cytochrome P450 1A and 3A activity and gene expression. 2. Using porcine microsomes, we demonstrated that RES caused non-competitive inhibition of CYP1A activity and un-competitive inhibition of CYP3A activity...
March 19, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28298174/the-involvement-of-multidrug-and-toxin-extrusion-protein-1-in-the-distribution-and-excretion-of-berberine
#2
Ling Xiao, Yaru Xue, Cuifeng Zhang, Le Wang, Yunfei Lin, Guoyu Pan
1. Berberine (BBR), an isoquinoline alkaloid, has demonstrated multiple clinical pharmacological actions. As a substrate of multiple transporters in the liver, BBR is rarely excreted into the bile but can be found in the urine. The purpose of the present study was to investigate the role of multidrug and toxin extrusion protein 1 (MATE1) in the transport of BBR in the liver and kidney. 2. Using human MATE1 (hMATE1)-transfected HEK293 cells, BBR was shown to be a substrate of hMATE1 (Km = 4.28 ± 2.18 μM)...
March 16, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28294690/stereoselective-and-non-stereoselective-pharmacokinetics-of-rabeprazole-an-overview
#3
Ranjeet Prasad Dash, Rana Rais, Nuggehally R Srinivas
1. Proton pump inhibitors have been extensively used for the treatment of ailments due to increased gastric acid secretion such as peptic ulcers, gastroesophageal reflux disease etc. 2. There are several approved drugs in the proton pump inhibitor class with the latest entries representing single enantiomer drugs of the previously approved racemic drugs. 3. Despite having a high degree of structural resemblance, rabeprazole, was shown to possess some unique differentiation from other drugs in the class. One of the key distinguishing features of rabeprazole was related to the lesser involvement of polymorphic metabolism in its pharmacokinetic disposition...
March 15, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28290233/area-under-the-curve-predictions-of-dalbavancin-a-new-lipoglycopeptide-agent-using-the-end-of-intravenous-infusion-concentration-data-point-by-regression-analyses-such-as-linear-log-linear-and-power-models
#4
Ravi Kanth Bhamidipati, Muzeeb Syed, Ramesh Mullangi, Nuggehally Srinivas
1. Dalbavancin, a lipoglycopeptide, is approved for treating gram-positive bacterial infections. Area under plasma concentration versus time curve (AUCinf) of dalbavancin is a key parameter and AUCinf/MIC ratio is a critical pharmacodynamic marker. 2. Using end of intravenous infusion concentration (i.e. Cmax) Cmax versus AUCinf relationship for dalbavancin was established by regression analyses (i.e. linear, log-log, log-linear and power models) using 21 pairs of subject data. 3. The predictions of the AUCinf were performed using published Cmax data by application of regression equations...
March 14, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28287856/enzymatic-kinetics-regarding-reversible-metabolism-of-cs-0777-a-sphingosine-1-phosphate-receptor-modulator-via-phosphorylation-and-dephosphorylation-in-humans
#5
Shin-Ichi Inaba, Maki Yamaguchi-Goto, Kaoru Tanaka-Takanaka, Kiyoaki Yonesu, Hidetaka Sakurai, Kazuishi Kubota, Takashi Izumi
1. CS-0777, a candidate compound for autoimmune diseases, becomes phosphorylated active metabolite, M1, by fructosamine 3-kinase (FN3K), FN3K-related protein (FN3K-RP); and M1 reverted back to CS-0777 by alkaline phosphatase (ALP) in the body. We performed enzyme kinetic analysis of phosphorylation of CS-0777 by FN3K, FN3K-RP, human erythrocytes and human platelets; and dephosphorylation of M1 by various ALP isozymes and human liver, kidney, lung and small intestine microsomes. 2. The Michaelis constants of human FN3K, FN3K-RP, and erythrocytes for CS-0777 phosphorylation were in the range from 498 μM to 1060 μM...
March 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28287050/the-effect-of-fenofibric-acid-on-the-pharmacokinetics-and-pharmacodynamics-of-warfarin-in-rats
#6
Chaorui Guo, Siqi Xue, Xiufen Zheng, Lu Yang, Di Zhao, Xijing Chen, Ning Li
1. Case reports have shown that coadministration of fenofibric acid (FA) could increase bleeding risks of warfarin, but the mechanisms remained unknown. We therefore investigated the pharmacokinetic and pharmacodynamic interaction between warfarin and FA in rats. 2. Rats received warfarin alone (2 mg/kg) or coadministered with FA (100 mg/kg). FA significantly increased the exposure to warfarin, and decreased that to 7-hydroxywarfarin in rats nearly by two-fold, meanwhile increased Cmax and prolonged t1/2 of warfarin...
March 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28287022/metabolic-map-of-osthole-and-its-effect-on-lipids
#7
Qi Zhao, Xin-Mei Li, Hong-Ning Liu, Frank J Gonzalez, Fei Li
1. Osthole, a coumarin compound from plants, is a promising agent for the treatment of metabolic diseases, including hyperglycemia, fatty liver, and cancers. Studies indicate that the peroxisome proliferator-activated receptors (PPAR) α and γ are involved in the pharmacological effects of osthole. The in vitro and in vivo metabolism of osthole, and its biological activity are not completely understood. 2. In this study, UPLC-ESI-QTOFMS-based metabolomics was used to determine the metabolic pathway of osthole and its influence on the levels of endogenous metabolites...
March 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28285550/the-inhibition-of-udp-glucuronosyltransferases-ugts-by-tetraiodothyronine-t4-and-triiodothyronine-t3
#8
Da-Wei Chen, Zuo Du, Chun-Ze Zhang, Wei-Hua Zhang, Yun-Feng Cao, Hong-Zhi Sun, Zhi-Tu Zhu, Kun Yang, Yong-Zhe Liu, Ze-Wei Zhao, Zhi-Wei Fu, Wen-Qing Gu, Yang Yu, Zhong-Ze Fang
1. UDP-glucuronosyltransferases (UGTs) are important drug-metabolizing enzymes (DMEs) catalyzing the glucuronidation elimination of various xenobiotics and endogenous substances. Endogenous substances are important regulators for the activity of various UGT isoforms. Triiodothyronine (T3) and thyroxine (T4) are important thyroid hormones essential for normal cellular differentiation and growth. The present study aims to elucidate the inhibition behavior of T3 and T4 on the activity of UGT isoforms. 2. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to screen the inhibition potential of triiodothyronine (T3) and thyroxine (T4) on the activity of various UGT isoforms...
March 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27830982/excretion-and-toxicity-evaluation-of-131-i-sennoside-a-as-a-necrosis-avid-agent
#9
Zhiqi Yin, Lidan Sun, Qiaomei Jin, Shaoli Song, Yuanbo Feng, Hong Liao, Yicheng Ni, Jian Zhang, Wei Liu
1. Sennoside A (SA) is a newly identified necrosis-avid agent that shows capability for imaging diagnosis and tumor necrosis targeted radiotherapy. As a water-soluble compound, (131)I-Sennoside A ((131)I-SA) might be excreted predominately through the kidneys with the possibility of nephrotoxicity. 2. To further verify excretion pathway and examine nephrotoxicity of (131)I-SA, excretion and nephrotoxicity were appraised. The pharmacokinetics, hepatotoxicity and hematotoxicity of (131)I-SA were also evaluated to accelerate its possible clinical translation...
March 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28281401/a-novel-in-vitro-allometric-scaling-methodology-for-aldehyde-oxidase-substrates-to-enable-selection-of-appropriate-species-for-traditional-allometry
#10
Rachel D Crouch, J Matthew Hutzler, J Scott Daniels
1. Failure to predict human pharmacokinetics of aldehyde oxidase (AO) substrates using traditional allometry has been attributed to species differences in AO metabolism. 2. To identify appropriate species for predicting human in vivo clearance by single-species scaling (SSS) or multispecies allometry (MA), we scaled in vitro intrinsic clearance (CLint) of five AO substrates obtained from hepatic S9 of mouse, rat, guinea pig, monkey and minipig to human in vitro CLint. 3. When predicting human in vitro CLint, average absolute fold-error was ≤2...
March 10, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28281396/characterization-of-metabolites-of-larotaxel-in-rat-by-liquid-chromatography-coupled-with-q-exactive-high-resolution-benchtop-quadrupole-orbitrap-mass-spectrometer
#11
Zhenzhen Liu, Pengyi Hou, Lian Liu, Feng Qian
1. Liquid-chromatography (LC) high-resolution (HR) mass spectrometry (MS) analysis can record HR full scans for drug metabolism studies. Larotaxel is a taxane analog that has the potential for the treatment of various types of cancer. 2. In this study, the metabolism of larotaxel was evaluated after an intravenous dose of 8 mg/kg via the caudal vein to healthy rats and its metabolites were characterized by high performance liquid chromatography coupled with a Q Exactive high-resolution benchtop quadrupole orbitrap mass spectrometer...
March 10, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28281384/transport-properties-of-valsartan-sacubitril-and-its-active-metabolite-lbq657-as-determinants-of-disposition
#12
Imad Hanna, Natalya Alexander, Matthew H Crouthamel, John Davis, Adrienne Natrillo, Phi Tran, Arpine Vapurcuyan, Bing Zhu
1. The potential for drug-drug interactions of LCZ696 (a novel, crystalline complex comprising sacubitril and valsartan) was investigated in vitro. 2. Sacubitril was shown to be a highly permeable P-glycoprotein (P-gp) substrate and was hydrolyzed to the active anionic metabolite LBQ657 by human carboxylesterase 1 (CES1b and 1c). The multidrug resistance-associated protein 2 (MRP2) was shown to be capable of LBQ657 and valsartan transport that contributes to the elimination of either compound. 3. LBQ657 and valsartan were transported by OAT1, OAT3, OATP1B1 and OATP1B3, whereas no OAT- or OATP-mediated sacubitril transport was observed...
March 10, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28277163/predictions-of-bisphenol-a-hepatic-clearance-in-the-isolated-perfused-rat-liver-iprl-impact-of-albumin-binding-and-of-co-administration-with-naproxen
#13
Sara Bounakta, Michel Bteich, Marc Mantha, Patrick Poulin, Sami Haddad
1. This study aimed (i) to characterise hepatic clearance (CL) of bisphenol A (BPA) and naproxen (NAP) administered alone or in binary mixtures to highlight the influence of a binding to albumin (ALB) using an isolated perfused rat liver (IPRL) system; and (ii) to compare results of prediction algorithms with measured clearance rates. 2. The IPRL system and liver microsomes were used to determine the metabolic constants of BPA and NAP either in the presence or absence of ALB. In this study, the IPRL was used as proxy for the in vivo situation...
March 3, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28277164/pharmacokinetics-of-the-selective-prostacyclin-receptor-agonist-selexipag-in-rats-dogs-and-monkeys
#14
Tomohiko Ichikawa, Tetsuhiro Yamada, Alexander Treiber, Carmela Gnerre, Kiyoko Nonaka
1. This study examined the pharmacokinetics, distribution, metabolism and excretion of the selective prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-33679). The compounds were investigated following oral and/or intravenous administration to intact rats, dogs and monkeys, and bile-duct-cannulated rats and dogs. 2. After oral administration of [(14)C]selexipag, selexipag was well absorbed in rats and dogs with total recoveries of over 90% of the dose, mainly in the faeces...
March 2, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28277165/xenobiotic-c-sulfonate-derivatives-metabolites-or-metabonates
#15
Stephen C Mitchell
1. The production of sulfate conjugates is a well-known and established pathway within the field of xenobiotic metabolism. In addition to the usual attachment of a sulfonate grouping via an oxygen atom (O-sulfonates) to yield a sulfate conjugate, so-called "N-sulfates" (N-sulfonates) have been reported and "S-sulfates" (S-sulfonates) mooted to exist. 2. The few examples cited in the literature where the sulfur atom of the sulfonate group was attached directly to a carbon atom of the xenobiotic (C-sulfonates) and subsequently excreted as a metabolite have been collated, examined and reviewed...
February 28, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28166443/aldehyde-oxidase-dependent-species-difference-in-hepatic-metabolism-of-fasudil-to-hydroxyfasudil
#16
Zhengsheng Mao, Yali Wu, Qiuying Li, Xin Wang, Youping Liu, Xin Di
1. An investigation on the metabolic mechanism of fasudil to hydroxyfasudil was conducted in vitro using liver subcellular fractions of different species. Hydroxyfasudil was generated in large amounts by male rat liver S9 and to a similar extent by human liver S9 but was not detected in dog liver S9 incubations. 2. Studies with various molybdenum hydroxylase inhibitors demonstrated that aldehyde oxidase (AO), but not xanthine oxidase (XO), selectively catalyzed fasudil to hydroxyfasudil in both rat and human liver cytosol...
February 6, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28092216/metabolism-of-metofluthrin-in-rats-i-identification-of-metabolites
#17
Jun Abe, Hirohisa Nagahori, Hirokazu Tarui, Yoshitaka Tomigahara, Naohiko Isobe
1. Metofluthrin (2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (Z/E)-(1R)-trans-2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate) is a novel pyrethroid insecticide, which has E/Z isomers at prop-1-enyl group. 2. Rats were orally dosed with each [(14)C]-labelled E/Z isomer, and the excreta were collected for isolation and identification of metabolites. Analysis of the excreta by LC/MS and NMR revealed formation of 33 and 23 (total 42) metabolites from rats dosed with Z-isomer and E-isomer, respectively...
February 5, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28084139/a-high-frequency-missense-sult1b1-allelic-variant-l145v-selectively-expressed-in-african-descendants-exhibits-altered-kinetic-properties
#18
Zachary E Tibbs, Amber L Guidry, Josie L Falany, Susan A Kadlubar, Charles N Falany
1. Human cytosolic sulfotransferase 1B1 (SULT1B1) sulfates small phenolic compounds and bioactivates polycyclic aromatic hydrocarbons. To date, no SULT1B1 allelic variants have been well-characterized. 2. While cloning SULT1B1 from human endometrial specimens, an allelic variant resulting in valine instead of leucine at the 145th amino acid position (L145V) was detected. NCBI reported this alteration as the highest frequency SULT1B1 allelic variant. 3. L145V frequency comprised 9% of 37 mixed-population human patients and was specific to African Americans with an allelic frequency of 25%...
February 5, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28145791/human-plasma-metabolic-profiles-of-benzydamine-a-flavin-containing-monooxygenase-probe-substrate-simulated-with-pharmacokinetic-data-from-control-and-humanized-liver-mice
#19
Miho Yamazaki-Nishioka, Makiko Shimizu, Hiroshi Suemizu, Megumi Nishiwaki, Marina Mitsui, Hiroshi Yamazaki
1. Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir. 2. Following oral administration of benzydamine (10 mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine...
February 1, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28093031/the-inhibitory-effects-of-five-alkaloids-on-the-substrate-transport-mediated-through-human-organic-anion-and-cation-transporters
#20
Tahiatul Shams, Xiaoxi Lu, Ling Zhu, Fanfan Zhou
1. Human solute carrier transporters (SLCs) are important membrane proteins mediate the cellular transport of many endogenous and exogenous substances. Organic anion/cation transporters (OATs/OCTs) and organic anion transporting polypeptides (OATPs) are essential SLCs involved in drug influx. Drug-drug/herb interactions through competing for specific SLCs often lead to unsatisfied therapeutic outcomes and/or unwanted side effects. In this study, we comprehensively investigated the inhibitory effects of five clinically relevant alkaloids (dendrobine, matrine, oxymatrine, tryptanthrin and chelerythrine) on the substrate transport through several OATs/OCTs and OATPs...
February 1, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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