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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://read.qxmd.com/read/30747554/investigation-of-the-inhibition-of-eight-major-human-cytochrome-p450-isozymes-by-a-probe-substrate-cocktail-in-vitro-with-emphasis-on-cyp2e1
#1
Guru R Valicherla, Amrut Mishra, Srinivas Lenkalapelly, Bhupathi Jillela, Femi M Francis, Lakshman Rajagopalan, Pratima Srivastava
1. A protocol has been developed and validated for the high throughput screening of eight major human cytochrome P450 (CYP) isozymes inhibition (CYP 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, 2C8 and 2E1) using an in vitro probe cocktail containing eight substrates by overcoming the unfavorable effect of assay conditions on CYP2E1 inhibition data. 2. The cocktail consisting of selective probe substrates like Tacrine (CYP1A2), Diclofenac (CYP2C9), S-Mephenytoin (CYP2C19), Dextromethorphan (CYP2D6), Midazolam (CYP3A4), Bupropion (CYP2B6), Paclitaxel (CYP2C8) and Chlorzoxazone (CYP2E1) was incubated with human liver microsomes...
February 12, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30747552/metabolism-and-excretion-of-s-6-3-cyclopentyl-2-4-trifluoromethyl-1h-imidazol-1-yl-propanamido-nicotinic-acid-pf-04991532-a-hepatoselective-glucokinase-activator-in-humans-confirmation-of-the-mist-potential-noted-in-first-in-human-metabolite-scouting-studies
#2
Raman Sharma, Arthur Bergman, John Litchfield, Karen Atkinson, David J Kazierad, Amit S Kalgutkar
1. The absorption, metabolism, and excretion of a single oral 450-mg dose of [14C]-(S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid (PF-04991532), a hepatoselective glucokinase activator, was investigated in humans. Mass balance was achieved with ∼94.6% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 70.6% and 24.1%, respectively. Unchanged PF-04991532 collectively accounted for ∼47.2% of the dose excreted in feces and urine, suggestive of moderate metabolic elimination in humans...
February 12, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30747549/identification-of-novel-glutathione-conjugates-of-terbinafine-in-liver-microsomes-and-hepatocytes-across-species
#3
Amol Patil, Mayurbhai Kathadbhai Ladumor, Shyam H Kamble, Benjamin M Johnson, Murali Subramanian, Michael W Sinz, Dilip Kumar Singh, Sivaprasad Putlur, Priyadeep Bhutani, Deepak Suresh Ahire, Saranjit Singh
1. Terbinafine (TBF), a common antifungal agent, has been associated with rare incidences of hepatotoxicity. It is hypothesized that bioactivation of TBF to reactive intermediates and subsequent binding to critical cellular proteins may contribute to this toxicity. In the present study, we have characterized the bioactivation pathways of TBF extensively in human, mouse, monkey, dog and rat liver microsomes and hepatocytes. 2. A total of twenty glutathione conjugates of TBF were identified in hepatocytes; thirteen of these conjugates were also detected in liver microsomes...
February 12, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30747023/human-mass-balance-pharmacokinetics-and-metabolism-of-rovatirelin-and-identification-of-its-metabolic-enzymes-in-vitro
#4
Kaoru Kobayashi, Yoshikazu Abe, Asuka Kawai, Takao Furihata, Hiroshi Harada, Takuro Endo, Hiroo Takeda
1. The mass balance, pharmacokinetics and metabolism of rovatirelin were characterised in healthy male subjects after a single oral dose of [14 C]rovatirelin. [14 C]Rovatirelin was steadily absorbed, and the peak concentrations of radioactivity and rovatirelin were observed in plasma at 5-6 h after administration. The AUCinf of radioactivity was 4.9-fold greater than that of rovatirelin. Rovatirelin and its metabolite (thiazoylalanyl)methylpyrrolidine (TAMP) circulated in plasma as the major components. The total radioactivity recovered in urine and faeces was 89...
February 12, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30744481/prediction-of-human-pharmacokinetics-of-long-half-life-compounds-using-chimeric-mice-with-humanised-liver
#5
Maki Miyamoto, Shinji Iwasaki, Ikumi Chisaki, Sayaka Nakagawa, Nobuyuki Amano, Yohei Kosugi, Hideki Hirabayashi
1. The prediction of human pharmacokinetic (PK) parameters is an important theme to select drug candidates from preclinical studies. It is essential to improve the prediction accuracy of compound half-life (t1/2 ) in humans. In this study, the predictability of t1/2 in humans using PXB mice®, chimeric mice with humanised liver, was assessed using 14 compounds showing long t1/2 in humans. 2. After intravenous administration of the compounds to PXB mice, the plasma concentration-time profiles were fitted using one- or two-compartment models and the human clearance (CLt ) and distribution volume (Vdss ) were predicted from single-species scaling...
February 12, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30741588/effects-of-liquorice-on-pharmacokinetics-of-aconitine-in-rats
#6
Yufei He, Zihong Wei, Xiaoyan Ci, Ying Xie, Xiulin Yi, Yong Zeng, Yazhuo Li, Changxiao Liu
1. Aconite alkaloids are the main bioactive ingredients existing in aconitum, for instance aconitine, which exhibit potent analgesic, antirheumatic and other pharmacological effects. In this study, effects of long-term treatment with liquorice on pharmacokinetics of aconitine in rats were investigated. 2. Pharmacokinetics of aconitine after oral administration of aconitine at 1.5 mg/kg either with pretreatment of liquorice water extract at 0.433 g/kg or 1.299 g/kg (crude drug) respectively for one week or not were studied...
February 11, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30741064/lc-ms-ms-detection-of-citrus-unshiu-peel-derived-flavonoids-in-the-plasma-and-brain-after-oral-administration-of-yokukansankachimpihange-in-rats
#7
Mikina Takiyama, Takashi Matsumoto, Junko Watanabe
1. Yokukansankachimpihange (YKSCH), a Kampo formulation combining Citrus unshiu peel (CUP) and Pinellia tuber (PT) with yokukansan (YKS), has been recently used to treat the behavioral and psychological symptoms of dementia. Several flavonoids derived from CUP and PT reportedly exhibit psychopharmacological activity, but it remains unclear whether these flavonoids reach the brain after oral administration of YKSCH. 2. In this study, we first measured eight target flavonoids in the plasma and brain in rats orally administered YKSCH...
February 11, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30739533/enzymatic-analysis-of-glucuronidation-of-synthetic-cannabinoid-1-naphthyl-1-4-fluorobenzyl-1h-indole-3-carboxylate-fdu-pb-22
#8
Sabrina Jones, Azure L Yarbrough, Amal Shoeib, John M Bush, William E Fantegrossi, Paul L Prather, Anna Radominska-Pandya, Ryoichi Fujiwara
Recently, there has been a rise in abuse of synthetic cannabinoids (SCBs). The consumption of SCBs results in various effects and can induce toxic reactions, including paranoia, seizures, tachycardia, and even death. 1-Naphthyl 1-(4-fluorobenzyl)-1H-indole-3-carboxylate (FDU-PB-22) is a third generation SCB whose metabolic pathway has not been fully characterized. 2. In this study, we conducted in vitro pharmacokinetic analysis of FDU-PB-22 metabolism. 3. Metabolic reactions containing FDU-PB-22 and human liver microsomes (HLMs) were independent of NADPH but not UDP-glucuronic acid (UDPGA), suggesting that UDP-glucuronosyltransferases (UGTs) are the primary enzymes involved in this metabolism...
February 9, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30729838/comparison-of-pharmacokinetics-of-phytoecdysones-and-triterpenoid-saponins-of-monomer-crude-and-processed-radix-achyranthis-bidentatae-by-uhplc-ms-ms
#9
Liu Yang, Hai Jiang, Meiling Yan, Xudong Xing, Xinyue Guo, Wenjing Man, Ajia Hou, Bingyou Yang, Qiuhong Wang, Haixue Kuang
1. The aim of this study was to develop a selective, rapid, accurate and sensitive ultrahigh performance liquid chromatography tandem mass spectrometry method for pharmacokinetic (PK) studies of phytoecdysones and triterpenoid saponins after oral administration of five monomers, crude, wine-processed and salt-processed Radix Achyranthis bidentatae. 2. A Thermo Hypersil GOLD C18 column (100 mm× 2.1 mm, 1.9μm) coupled with a mobile phase of (A) acetonitrile and (B) water (both containing 0.3% acetic acid) was used for sample separation...
February 7, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30724651/effects-of-cyp2c11-gene-knockout-on-the-pharmacokinetics-and-pharmacodynamics-of-warfarin-in-rats
#10
Huanying Ye, Danjuan Sui, Wei Liu, Yuannan Yuan, Zhen Ouyang, Yuan Wei
1. CYP2C11 is the most abundant isoform of CYPs in male rats and is considered the main enzyme for warfarin metabolism. 2. To further access the in vivo function of CYP2C11 in warfarin metabolism and efficacy, a CYP2C11-null rat model was used to study warfarin metabolism with both in vitro and in vivo approaches. Prothrombin time (PT) of warfarin was also determined. 3. The maximum rate of metabolism (Vmax ) and intrinsic clearance (CLint ) of liver microsomes from CYP2C11-null males were reduced by 37% and 64%, respectively, compared to those in Sprague Dawley (S-D) rats...
February 6, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30714842/conflicting-alterations-in-hepatic-expression-of-cyp3a-and-enzyme-kinetics-in-rats-exposed-to-5-fluorouracil-relevance-to-pharmacokinetics-of-midazolam
#11
Shuhei Fukuno, Katsuhito Nagai, Mai Fujiike, Yuya Sasaki, Hiroki Konishi
1. 5-Fluorouracil (5-FU) is a pyrimidine derivative widely used for the treatment of cancer. In this study, we investigated the effects of 5-FU on the protein expression of hepatic CYP3A and their enzyme activity for metabolizing midazolam (MDZ), a typical substrate of CYP3A, in rat liver microsomes. We also examined the pharmacokinetic behavior of intravenously administered MDZ in rats treated with 5-FU (120 mg/kg, ip). 2. 5-FU was shown to induce hepatic CYP3A2 protein 2 days after administration without changing the expression of CYP3A1/3A23...
February 4, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30694093/an-evaluation-of-metabolite-profiling-of-six-drugs-using-dried-blood-spot
#12
Kishore K Katyayan, Yu-Hua Hui
1. Dry blood spot (DBS) analysis has been extensively used for the quantitative analysis of drugs by mass spectrometry; however, utilization of DBS for qualitative metabolite profiling has been very limited. 2. In the present study, we investigated the use of DBS for metabolite profiling of genistein, carbamazepine, losartan, sunitinib, sildenafil, and zoniporide representing a range of Phase I and Phase II biotransformations following oral and intravenous dosing to rats. Plasma and DBS were collected for PK and metabolite profiling...
January 29, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30654691/pharmacokinetics-behaviors-of-l-menthol-after-inhalation-and-intravenous-injection-in-rats-and-its-inhibition-effects-on-cyp450-enzymes-in-rat-liver-microsomes
#13
Xiuli Feng, Yan Liu, Xiao Sun, Ang Li, Xiaoyan Jiang, Xiaosong Zhu, Zhongxi Zhao
1. L-menthol, as a kind of monocyclic terpene, is widely used in inhalation formulations, food and tobacco. The purpose of this study was to investigate the pharmacokinetic behavior of l-menthol as well as its influence on the activities of cytochrome P450 enzymes. 2. The pharmacokinetic behaviors of l-menthol after inhalation (50 mg/kg) and intravenous injection (10 mg/kg) were investigated. A rat liver microsomal model was adopted to elucidate the inhibitory effect of l-menthol on CYP1A2, CYP2C11, CYP2D1/2, CYP2D4, CYP2E1, and CYP3A1 using phenacetin, tolbutamide, omeprazole, dextromethorphan, chlorzoxazone and testosterone as probe drugs, respectively...
January 18, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30654682/metabolism-study-of-hesperetin-and-hesperidin-in-rats-by-uhplc-ltq-orbitrap-ms-n
#14
Qishu Jiao, Lulu Xu, Lijuan Jiang, Yanyan Jiang, Jiayu Zhang, Bin Liu
1. Hesperidin (HPD) and hesperetin (HPT), as a kind of flavonone compounds, are abundant in citrus fruits with various pharmacological effects. HPD and HPT are not always consistent in some biological activities, even if they have the same skeletal structure. 2. The aim of this study was to screen and identify HPT and HPD metabolites in rats using UHPLC-LTQ-Orbitrap MSn , compare the possible metabolism and provide the research basis for further understanding the similarities and differences in pharmacodynamics and pharmacokinetics of HPT and HPD...
January 18, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30623698/comparative-study-on-the-metabolism-of-the-ergot-alkaloids-ergocristine-ergocryptine-ergotamine-and-ergovaline-in-equine-and-human-s9-fractions-and-equine-liver-preparations
#15
Wiebke Rudolph, Daniela Remane, Dirk K Wissenbach, Frank T Peters
1. Ergopeptine alkaloids like ergovaline and ergotamine are suspected to be associated with fescue toxicosis and ergotism in horses. Information on the metabolism of ergot alkaloids is scarce, especially in horses, but needed for toxicological analysis of these drugs in urine/feces of affected horses. The aim of this study was to investigate the metabolism of ergovaline, ergotamine, ergocristine, and ergocryptine in horses and comparison to humans. 2. Supernatants of alkaloid incubations with equine and human liver S9 fractions were analyzed by reversed-phase liquid-chromatography coupled to high-resolution tandem mass spectrometry with full scan and MS2 acquisition...
January 9, 2019: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30596462/regioselective-hydroxylation-of-an-antiarrhythmic-drug-propafenone-mediated-by-rat-liver-cytochrome-p450-2d2-differs-from-that-catalyzed-by-human-p450-2d6
#16
Shotaro Uehara, Norie Murayama, Hiroshi Yamazaki, Hiroshi Suemizu
1. Propafenone, an antiarrhythmic drug, is a typical human cytochrome P450 (P450) 2D6 substrate used in preclinical studies. Here, propafenone oxidation by mammalian liver microsomes was investigated in vitro. 2. Liver microsomes from humans and marmosets preferentially mediated propafenone 5-hydroxylation, minipig, rat and mouse livers primarily mediated 4'-hydroxylation, but cynomolgus monkey and dog liver microsomes differently mediated N-despropylation. 3. Quinine, ketoconazole or anti-P450 2D antibodies suppressed propafenone 4'/5-hydroxylation in human and rat liver microsomes...
December 31, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30589368/predictability-of-human-pharmacokinetics-of-diisononyl-phthalate-dinp-using-chimeric-mice-with-humanized-liver
#17
Hiroshi Iwata, Masatomo Goto, Norifumi Sakai, Hiroshi Suemizu, Hiroshi Yamazaki
1. In order to investigate the pharmacokinetics of diisononyl phthalate (DINP) in humans, we administered [phenyl-U-14 C]DINP at a dose of 50.0 mg/kg orally to chimeric mice (humanized-liver mice) in which the liver of TK-NOG mice (control mice) was replaced with human hepatocytes. 2. The plasma radioactivity concentrations peaked (18.0 and 59.9 µg equivalent of DINP/mL, respectively) at 2 h after administration in control and humanized-liver mice. Concentrations rose again at 8 h in controls, but not in humanized-liver mice...
December 27, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30588869/differential-pharmacokinetic-drug-drug-interaction-potential-of-eletriptan-between-oral-and-subcutaneous-routes
#18
Harilal Patel, Nirmal Desai, Prakash Patel, Nirav Modi, Krunal Soni, Nitin Dobaria, Nuggehally R Srinivas
1. Pharmacokinetic drug-drug interaction (DDI) data is important from a label claim either in combination drug usage or in polypharmacy situation. 2. Eletriptan undergoes first pass related metabolism through CYP3A4 enzyme to form pharmacologically active N-desmethyl metabolite. 3. Differential DDI interaction of the concomitant oral dosing of ketoconazole (20.1 mg/kg), a CYP3A4 inhibitor, with oral (4.2 mg/kg) or subcutaneous dose (2.1 mg/kg) of eletriptan was evaluated in male Sprague Dawley rats. Serial pharmacokinetic samples were collected and simultaneously analysed for eletriptan/N-desmethyl eletriptan using validated assay...
December 27, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30587071/an-in-vivo-evaluation-of-the-ontogeny-of-stereoselective-fluoxetine-metabolism-and-disposition-in-lambs-from-birth-to-one-year-of-age
#19
Timothy W Chow, Tuan-Anh Nguyen, K Wayne Riggs, Dan W Rurak
1. The objective was to determine the ontogeny of stereoselective fluoxetine (FX) disposition in postnatal sheep from newborn to adulthood. 2. Catheters were implanted in a carotid artery and jugular vein. FX was administered intravenously, followed by serial arterial blood and cumulative urine collection. The concentrations of R,S-FX and R,S-norfluoxetine (R,S-NFX) in samples were measured using a validated enantioselective LC/MS/MS analytical method. 3. The metabolism of FX at 4.2 ± 0.4 days was limited compared to adults, but had developed compared to the fetus...
December 27, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://read.qxmd.com/read/30587068/effects-of-mdr1-1236c-t-2677g-t-3435c-t-polymorphisms-on-the-intracellular-accumulation-of-tacrolimus-cyclosporine-a-sirolimus-and-everolimus
#20
Rong Wang, Xuan Sun, Yong-Shu Deng, Xu-Wen Qiu
1. Overexpression of P-glycoprotein (P-gp, encoded by MDR1) mediates resistance to multiple immunosuppressors. Several common MDR1 variants (1236C > T, 2677G > T, 3435C > T) impact the efflux activity of P-gp- mediated substrates. We assessed the effect of these polymorphisms on the sensitivity, intracellular accumulation, and efflux of tacrolimus, cyclosporine A, sirolimus, and everolimus in transfected LLC-PK1 cells. 2. LLC-PK1 cell lines were transfected with empty vector (pcDNA3.1) and recombinant MDR1T-T-T , MDR1C-T-T , MDR1C-G-T , and MDR1C-G-C vectors, respectively and further screened in the presence of puromycin...
December 27, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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