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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/30028220/the-current-understanding-of-the-interactions-between-nanoparticles-and-cytochrome-p450-enzymes-a-literature-based-review
#1
Pan Yan, Chin Eng Ong, Yuh Fen Pung, Jin Yu Chieng
1. Nanoparticles (NPs) have a wide spectrum applications in the areas of industry and biomedicine. However, concerns of their toxic and negative impacts on the environments as well as human health have been raised. Cytochrome P450s (CYPs) are involved in endogenous and exogenous metabolism. Modulations of CYP can adversely damage drug metabolism, detoxification of xenobiotics and animal physiology functions. This review focused on NPs-CYP interactions for humans and animals available in the literature. 2. It was found that different NPs process specific inhibitory potencies against CYPs involved in drug metabolism...
July 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/30022699/inhibitor-selectivity-of-cnts-and-ents
#2
Balázs Vaskó, Viktória Juhász, Beáta Tóth, Anita Kurunczi, Zsolt Fekete, Joseph Krisjanis Zolnerciks, Emese Kis, Rémi Magnan, Axel Bidon-Chanal Badia, Marçal Pastor-Anglada, Eszter Hazai, Zsolt Bikadi, Ferenc Fülöp, Peter Krajcsi
1. The concentrative nucleoside transporters (CNT; solute carrier family 28 (SLC28)) and the equilibrative nucleoside transporters (ENT; solute carrier family 29 (SLC29)) are important therapeutic targets but may also mediate toxicity or adverse events. 2. To explore the relative role of the base and the monosaccharide moiety in inhibitor selectivity we selected compounds that either harbor an arabinose moiety or a cytosine moiety, as these groups had several commercially available drug members. 3. The screening data showed that more compounds harboring a cytosine moiety displayed potent interactions with the CNTs than compounds harboring the arabinose moiety...
July 19, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29985077/dioscorea-bulbifera-l-delays-the-excretion-of-doxorubicin-and-aggravates-doxorubicin-induced-cardiotoxicity-and-nephrotoxicity-by-inhibiting-the-expression-of-p-glycoprotein-in-mice-liver-and-kidney
#3
Xiaoyu Qu, Jinghui Zhai, Tingting Hu, Huan Gao, Lina Tao, Yueming Zhang, Yanqing Song, Sixi Zhang
1. We aimed to investigate the drug-drug interaction (DDI) between doxorubicin (DOX) and Dioscorea bulbifera L. (DB) solution in mice, and to explore the effect of P-glycoprotein (P-gp) on this type of DDI. 2. The toxicity of DOX in the liver, kidneys, and heart was assessed with alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea nitrogen (BUN), creatine kinase MB (CK-MB), creatine kinase (CK) and histopathology. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was used to determine the concentrations of DOX in the serum, liver, kidneys, and heart...
July 9, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29806508/disposition-and-metabolism-of-14-c-lemborexant-a-novel-dual-orexin-receptor-antagonist-in-rats-and-monkeys
#4
Takashi Ueno, Tomomi Ishida, Kazutomi Kusano
The disposition and metabolism of lemborexant, a novel dual orexin receptor antagonist currently under development as a therapeutic agent for insomnia disorder, were evaluated after a single oral administration of [14 C]lemborexant in Sprague-Dawley rats (10 mg/kg) and cynomolgus monkeys (3 mg/kg). In both species, [14 C]lemborexant was rapidly absorbed: radioactivity concentration in blood peaked at 0.83-1.8 h, and decreased with elimination half-life of 110 h. The radioactivity administered was excreted primarily into faeces, with relatively little excreted into urine...
July 5, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29972081/model-based-pharmacokinetic-and-pharmacodynamic-analysis-for-acute-effects-of-a-small-molecule-inhibitor-of-diacylglycerol-acyltransferase-1-in-the-tallyho-jngj-polygenic-mouse
#5
Yoon-Jee Chae, Jin Sook Song, Jin Hee Ahn, Myung Ae Bae, Kyeong-Ryoon Lee
The purpose of this study was to evaluate the acute effect of a small molecule inhibitor of DGAT-1 on triglycerides and cholesterol in polygenic type 2 diabetic TallyHo/JngJ (TH) mice. PF-04620110, a potent and selective DGAT-1 inhibitor, was used as a model compound in this study and which was administered to TH and ICR mice. The concentration of the model compound that produced 50% of maximum lowering of triglyceride level (IC50 ) in TH mice was not significantly different from that in ICR mice, when estimated using the model-based pharmacokinetic and pharmacodynamic assay, a 2-compartmental model and an indirect response model...
July 4, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29969338/expression-and-inducibility-of-cytochrome-p450s-in-human-hepatocytes-isolated-from-chimeric-mice-with-humanized-livers
#6
Shotaro Uehara, Yuichiro Higuchi, Nao Yoneda, Hiroshi Yamazaki, Hiroshi Suemizu
1. The evaluation of drug-mediated cytochrome P450 (P450) induction using human hepatocytes is important for predicting drug interactions. In this study, we prepared hepatocytes from chimeric mice with humanized livers (Hu-Liver mice) and evaluated the expression and inducibility of P450s in these hepatocytes. 2. Up to 95% of the Hu-Liver cells stained positive for human leukocyte antigen and the mean viability exceeded 85% (n = 10). Monolayer-cultured Hu-Liver cells displayed a similar morphology to cultures of the corresponding human hepatocytes used as transplantation donors...
July 3, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29962267/dose-proportionality-and-pharmacokinetics-of-dronedarone-following-intravenous-and-oral-administration-to-rat
#7
In-Hwan Baek
1. The aim of this study was to investigate the pharmacokinetic properties of dronedarone by using noncompartmental analysis and modeling approaches after intravenous and oral administration of dronedarone to rats. 2. Twenty-eight male Sprague-Dawley rats were randomly divided into four groups, and dronedarone was administered intravenously (1 mg/kg) and orally (5, 10, and 40 mg/kg) based on a parallel design. Blood samples were collected before and 0.083 (intravenous administration only), 0.25, 0.5, 0...
July 2, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29944058/modulation-of-transporter-activity-of-oatp1b1-and-oatp1b3-by-the-major-active-components-of-radix-ophiopogonis
#8
Lin Chen, Linlin Liu, Yu Chen, Mingyi Liu, Yuqing Xiong, Hong Zhang, Shibo Huang, Chunhua Xia
Radix Ophiopogonis is often an integral part of many traditional Chinese formulas, such as Shenmai injection used to treat cardio-cerebrovascular diseases. The present study aimed to investigate the influence of the four active components of Radix Ophiopogonis on the transport activity of OATP1B1 and OATP1B3. The uptake of rosuvastatin in OATP1B1-HEK293T cells were stimulated by methylophiopogonanone A (MA) and ophiopogonin D' (OPD') with EC50 calculated to be 11.33±2.78 and 4.62±0.64 μM, respectively. However, there were no remarkable influences on rosuvastatin uptake in the presence of methylophiopogonanone B (MB) or ophiopogonin D (OPD)...
June 26, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29790816/the-effect-of-elevated-%C3%AE-1-acid-glycoprotein-on-the-pharmacokinetics-of-tak-272-sco-272-an-orally-active-renin-inhibitor-in-rats
#9
Takuya Ebihara, Hisao Shimizu, Masami Yamamoto, Tomoaki Higuchi, Fumihiro Jinno, Yoshihiko Tagawa
The pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, was investigated in rats with subcutaneously injected turpentine oil, which was an inflammation animal model. Following intravenous administration of TAK-272 to the turpentine-treated rats, the systemic clearance and volume of distribution decreased with the elevated plasma α1 -acid glycoprotein (AGP) levels. The elevated plasma AGP levels were negatively correlated with the plasma unbound fraction of TAK-272 in the rats. Although the AUCs of total TAK-272 in the turpentine-treated rats were higher than those in the control rats after intravenous and oral administration, those of unbound TAK-272, which seem to directly contribute to the pharmacological effect and safety, were nearly equal between the turpentine-treated and control rats in the respective dose routes...
June 25, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29912608/liver-specific-knockout-of-histone-methyltransferase-g9a-impairs-liver-maturation-and-dysregulates-inflammatory-cytoprotective-and-drug-processing-genes
#10
Hong Lu, Xiaohong Lei, Qinghao Zhang
1. Methyltransferase G9a is essential for a key gene silencing mark, histone H3 dimethylation at lysine-9 (H3K9me2). Hepatic G9a expression is down-regulated by xenobiotics and diabetes. However, little is known about the role of G9a in liver. Thus, we generated mice with liver-specific knockout (Liv-KO) of G9a. 2. Adult G9a Liv-KO mice had marked loss of H3K9me2 proteins in liver, without overt liver injury or infiltration of inflammatory cells. However, G9a-null livers had ectopic induction of certain genes normally expressed in neural and immune systems...
June 18, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29808734/suitable-albumin-concentrations-for-enhanced-drug-oxidation-activities-mediated-by-human-liver-microsomal-cytochrome-p450-2c9-and-other-forms-predicted-with-unbound-fractions-and-partition-distribution-coefficients-of-model-substrates
#11
Kanami Shimura, Norie Murayama, Saki Tanaka, Shunsuke Onozeki, Hiroshi Yamazaki
Albumin has reportedly enhanced cytochrome P450 (P450)-mediated drug oxidation rates in human liver microsomes. Consequently, measurements of clearances and fractions metabolized could vary depending on the experimental albumin concentrations used. In this study, the oxidation rates of diclofenac and warfarin by human liver microsomes were significantly enhanced in the presence of 0.10% (w/v) bovine serum albumin, whereas those of tolbutamide and phenytoin required 1.0% and 2.0% of albumin for significant enhancement...
June 18, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29898636/effect-of-pretreatment-regimens-of-1-aminobenzotriazole-on-metabolism-and-gastric-emptying-of-probe-compounds-in-rat
#12
Shweta Padmanabhan, Harbeer Kaur, Abhijith Rao, Ajay Saxena, Yogesh Kumar Gupta, T Thanga Mariappan, Vinay K Holenarsipur
1. 1-Aminobenzotriazole (ABT) is a mechanism-based inactivator of major cytochrome P450 (CYP) enzymes, which is used in multiple mechanistic studies. 2. The purpose was to evaluate the effect of 2 h and 16 h pretreatment regimens of ABT on the exposures of triazolam in rat. Another objective was to evaluate the effect of ABT on gastric emptying of acetaminophen. 3. Plasma area under the curve (AUC) of triazolam was increased by 101-fold and 81-fold for the rats pre-treated with ABT at 2 h and 16 h, respectively, compared to control rats...
June 14, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29897827/a-metabolomic-perspective-of-pazopanib-induced-acute-hepatotoxicity-in-mice
#13
Yi-Kun Wang, Xiao-Nan Yang, Wei-Qing Liang, Yao Xiao, Qi Zhao, Xue-Rong Xiao, Frank J Gonzalez, Fei Li
1. To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. 2. A total of 22 pazopanib metabolites were identified in vitro and in vivo. Among these metabolites, 17 were novel, including several cysteine adducts and aldehyde derivatives. By screening using recombinant CYPs, CYP3A4 and CYP1A2 were found to be the main forms involved in the pazopanib hydroxylation. Formation of a cysteine conjugate (M3), an aldehyde derivative (M15) and two N-oxide metabolites (M18 and M20) from pazopanib could induce the oxidative stress that may be responsible in part for pazopanib-induced hepatotoxicity...
June 13, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29790809/characterization-of-in-vitro-and-in-vivo-metabolism-of-leelamine-using-liquid-chromatography-tandem-mass-spectrometry
#14
Riya Shrestha, Jung Jae Jo, DooHyun Lee, Taeho Lee, Sangkyu Lee
Leelamine is a diterpene compound found in the bark of pine trees and has garnered considerable interest owing to its potent anticancer properties. The aim of the present study was to investigate the metabolic profile of leelamine in human liver microsomes (HLMs) and mice using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that leelamine undergoes only Phase I metabolism, which generates one metabolite that is mono-hydroxylated at the C9 carbon of the octahydrophenanthrene ring (M1) both in vitro and in vivo...
June 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29889646/time-dependent-inhibition-tdi-of-cyp1a2-by-a-cyp3a4-mediated-reactive-metabolite-proposal-for-a-novel-mechanism-of-irreversible-tdi-by-a-non-suicide-substrate
#15
Haruka Nishimuta, Kimihiko Sato, Takao Watanabe, Masashi Yabuki
1. The purpose of the present study was to clarify the mechanism of DSP-1053 time-dependent inhibition (TDI) for CYP1A2. 2. DSP-1053 inhibited time- and concentration-dependently CYP1A2 activity in human liver microsomes even in a dilution assay. However, DSP-1053 was not metabolized by recombinant human CYP1A2. These findings indicate that the inhibitory effect of DSP-1053 on CYP1A2 does not follow a general mechanism-based inhibition because it didn't seem to be a suicide substrate. 3. In fact, CYP1A2 was not inhibited with DSP-1053 pre-incubation in recombinant human CYP1A2...
June 11, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29790806/bisphenol-s-modulates-concentrations-of-bisphenol-a-and-oestradiol-in-female-and-male-mice
#16
Tyler Pollock, Lucas J Greville, Rachel E Weaver, Marija Radenovic, Denys deCatanzaro
Concern over endocrine-disrupting actions of bisphenol A (BPA) has prompted some manufacturers to remove it from consumer products. Among the chemical replacements in "BPA-free" products are other bisphenol analogues, such as bisphenol S (BPS). Given evidence that BPA and BPS possess similar oestrogenic activity, their capacity to interact and disrupt oestrogen homeostasis should be examined. We investigated whether BPS can modulate concentrations of 14 C-BPA, exogenous 3 H-oestradiol (E2), or natural E2...
June 8, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29771166/prediction-of-volume-of-distribution-in-preclinical-species-and-humans-application-of-simplified-physiologically-based-algorithms
#17
Prashant B Nigade, Jayasagar Gundu, K Sreedhara Pai, Kumar V S Nemmani, Rashmi Talwar
The present study was aimed at developing simplified physiologically based semi-mechanistic algorithms to predict Vss and interspecies scaling factors to predict tissue-Kp s which require minimum input parameters, diminish the computing complexity and have better predictability. Vss of 86 structurally diverse compounds in preclinical species and 27 compounds in humans were predicted using only lung- and muscle-Kp as inputs. Interspecies scaling factor (s) were developed based on fold-differences in individual tissue lipid contents, relative organ blood flow: relative organ weight ratio between two species...
June 7, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29873579/impact-of-collagen-induced-arthritis-on-the-pharmacokinetic-disposition-of-voriconazole-a-widely-used-antifungal-agent-in-vitro-and-in-vivo-investigations-in-dba-1j-mice
#18
Poonam Giri, Prashant Delvadia, Lakshmikant Gupta, Priyal Trivedi, Nirmal Patel, Manoranjan Sharma, Jaideep Singh, Abhijit Chatterjee, Shekhar Kadam, Nuggehally R Srinivas
1. Pharmacokinetics of voriconazole, an anti-fungal agent, was determined in collagen-induced arthritic (CIA) and healthy DBA/1J mice. CIA was confirmed in DBA/1J mice by clinical scoring and histological analysis. 2. In vivo oral pharmacokinetic study (3 mg/kg) and in vitro stability assessment in liver microsomes were performed in CIA vs. healthy DBA/1J mice. Additionally, hepatic portal vein cannulated (HPVC) CIA and healthy mice were used to clarify the role of gut first-pass effect. Voriconazole/N-oxide metabolite was measured in plasma and in vitro samples using LC-MS/MS method...
June 6, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29768081/unremarkable-impact-of-oatp-inhibition-on-the-liver-concentration-of-fluvastatin-lovastatin-and-pitavastatin-in-wild-type-and-oatp1a-1b-knockout-mouse
#19
Jae H Chang, Xiaolin Zhang, Kirsten Messick, Yi-Chen Chen, Eugene Chen, Jonathan Cheong, Justin Ly
1. Oatp inhibitors have been shown to significantly increase the plasma exposure of statins. However, understanding alterations of liver concentration is also important. While modeling has simulated liver concentration changes, availability of experimental data is limited, especially when concerning drug-drug interactions (DDI). The objective of this work was to determine blood and liver concentrations of fluvastatin, lovastatin and pitavastatin, when blocking uptake transporters. 2. In wild-type mouse, rifampin pre-treatment decreased the unbound liver-to-plasma ratio (Kp,uu ) of fluvastatin by 4...
June 6, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29779438/metabolism-of-deltamethrin-and-cis-and-trans-permethrin-by-human-expressed-cytochrome-p450-and-carboxylesterase-enzymes
#20
Laura Hedges, Susan Brown, A Kenneth MacLeod, Audrey Vardy, Edward Doyle, Gina Song, Marjory Moreau, Miyoung Yoon, Thomas G Osimitz, Brian G Lake
The metabolism of the pyrethroids deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. DLM, CPM and TPM were metabolised by human CYP2B6 and CYP2C19, with the highest apparent intrinsic clearance (CLint ) values for pyrethroid metabolism being observed with CYP2C19. Other CYP enzymes contributing to the metabolism of one or more of the three pyrethroids were CYP1A2, CYP2C8, CYP2C9*1, CYP2D6*1, CYP3A4 and CYP3A5...
June 4, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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