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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/29781759/development-of-simultaneous-quantification-method-of-loteprednol-etabonate-le-and-its-acidic-metabolites-and-analysis-of-le-metabolism-in-rat
#1
Ahmed Samir, Ayano Kage, Ohura Kayoko, Teruko Imai
1. Loteprednol etabonate (LE) is a soft corticosteroid with two labile ester bonds at 17α- and 17β-positions. Its corticosteroidal activity disappears upon hydrolysis of either ester bond. Hydrolysis of both ester bonds produces the inactive metabolite, Δ1 -cortienic acid (Δ1 -CA). 2. The simple high performance liquid chromatography method using acetic acid gradient was developed for the simultaneous determination of LE and its acidic metabolites. 3. LE was hydrolyzed in rat plasma with a half-life of 9 minutes...
May 21, 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
#2
Laura Hedges, Susan Brown, A Kenneth MacLeod, Audrey Vardy, Edward Doyle, Gina Song, Marjory Moreau, Miyoung Yoon, Thomas G Osimitz, Brian G Lake
1. 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. 2. 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...
May 21, 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
#3
Prashant B Nigade, Jayasagar Gundu, K Sreedhara Pai, Kumar V S Nemmani, Rashmi Talwar
1. The present study was aimed at developing simplified physiologically based semi-mechanistic algorithms to predict Vss and interspecies scaling factors to predict tissue-Kps which require minimum input parameters, diminish the computing complexity and have better predictability. 2. 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...
May 17, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29770723/the-impact-of-azole-antifungal-drugs-on-imatinib-metabolism-in-human-liver-microsomes
#4
Xingxian Luo, Taifeng Li, Ze Yu, Xuecai Xue, Haiyang Zhao, Na Li, Liping Ma, Changqing Yang, Lin Huanglin, Wangyu Feng
1. Imatinib is widely used for the treatment of hematologic malignancies. It is common that imatinib is clinically co-prescribed with azole antifungal agents since these patients are more prone to invasive antifungal infection. The present study was to investigate the effects of azole antifungal drugs, including ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole on imatinib metabolism. 2. The main metabolites, 1-OH midazolam and N-desmethyl imatinib, were determined in the absence and in the presence of various levels of ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole...
May 17, 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
#5
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...
May 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29768080/effects-of-quercetin-on-the-pharmacokinetics-of-losartan-and-its-metabolite-exp3174-in-rats
#6
Qingling Zhao, Jinlan Wei, Hongying Zhang
1. This study investigates the influence of quercetin on the pharmacokinetics of losartan and its metabolite EXP3174 in rats. 2. The pharmacokinetic profiles of losartan and EXP3174 of orally administered losartan (10 mg/kg) with or without pretreatment with quercetin (20 mg/kg/day for 7 days) were investigated. Additionally, Caco-2 cell transwell model and rat liver microsome incubation experiments were also conducted to investigate its potential mechanism. 3. The results showed that when the rats were pretreated with quercetin, the Cmax (2...
May 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29737914/lipidomics-reveal-aryl-hydrocarbon-receptor-ahr-regulated-lipid-metabolic-pathway-in-alpha-naphthyl-isothiocyanate-anit-induced-intrahepatic-cholestasis
#7
Bao-Long Wang, Chang-Wen Zhang, Liang Wang, Kun-Long Tang, Naoki Tanaka, Frank J Gonzalez, Yong Xu, Zhong-Ze Fang
1. Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry (UPLC-ESI-QTOF MS)-based lipidomics was employ to elucidate new mechanism of alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. 2. Multiple lipid components significantly increased in ANIT-induced intrahepatic cholestasis, including PC 16:0, 20:4, PC 16:0, 22:6, PC 16:0, 18:2, LPC 18:2, PC 18:2, LPC 18:1, PC 18:1, 14:0, SM 18:1, 16:0, oleoylcarnitine, and palmitoylcarnitine...
May 8, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29708805/human-urinary-concentrations-of-monoisononyl-phthalate-estimated-using-physiologically-based-pharmacokinetic-modeling-and-experimental-pharmacokinetics-in-humanized-liver-mice-orally-administered-with-diisononyl-phthalate
#8
Tomonori Miura, Hiroshi Suemizu, Masatomo Goto, Norifumi Sakai, Hiroshi Iwata, Makiko Shimizu, Hiroshi Yamazaki
1. Diisononyl phthalate (DINP) used as a plasticizer is a mixture of compounds consisting of isononyl esters of phthalic acid. There are concerns about the bioaccumulation of such esters in humans. A [phenyl-U-14 C]DINP mixture was synthesized and orally administered (50 mg/kg body weight) to control and humanized-liver mice and their pharmacokinetics were determined. 2. Monoisononyl phthalate (MINP, a primary metabolite of DINP), oxidized MINP (isomers with hydroxy, carbonyl, and carboxy functional groups), and their glucuronides were detected in plasma from control and humanized-liver mice...
April 30, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29694257/functional-assessment-of-rat-pulmonary-flavin-containing-monooxygenase-activity
#9
Yildiz Yilmaz, Gareth Williams, Nenad Manevski, Markus Walles, Stephan Krähenbühl, Gian Camenisch
1. FMO expression varies extensively between human and commonly used preclinical species such as rat and mouse. The aim of this study was to investigate the pulmonary FMO activity in rat using benzydamine. Furthermore, the contribution of rat lung to the clearance of benzydamine was investigated using an in vivo pulmonary extraction model. 2. Benzydamine N-oxygenation was observed in lung microsomes and lung slices. Thermal inactivation of FMO and CYP inhibition suggested that rat pulmonary N-oxygenation is predominantly FMO mediated while any contribution from CYPs is negligible...
April 25, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29676197/pharmacokinetics-and-bioequivalence-of-two-strontium-ranelate-formulations-after-single-oral-administration-in-healthy-chinese-subjects
#10
Dan Zhang, Jingyi Ma, Aihua Du, Xiaolin Wang, Lina Zhang, Man Yang, Ming Deng, Huichen Liu
1. Pharmacokinetics of exogenous Sr and bioequivalence of a new oral formulation of strontium ranelate compared with the brand-name drug in healthy Chinese subjects was evaluated. 2. A balanced, randomized, single-dose, 2-treatment parallel study was conducted in 36 healthy Chinese subjects. Subjects were randomly allocated into two groups of 18 to receive a single oral dose of test formulation and reference formulation under a fasting state, respectively. Blood samples were collected at 19 designated time points up to 240 h post-dose...
April 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29676195/in-vitro-inhibitory-effects-of-sophocarpine-on-human-liver-cytochrome-p450-enzymes
#11
Jingwei Zhang, Chuansheng Li, Jingfa Zhang, Fan Zhang
1. Sophocarpine is a biologically active component isolated from the foxtail-like sophora herb and seed that is often orally administered for the treatment of cancer and chronic bronchial asthma. However, whether sophocarpine affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. 2. In this study, the inhibitory effects of sophocarpine on the eight human liver CYP isoforms (CYP1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes (HLMs)...
April 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29537356/metabolism-of-deltamethrin-and-cis-and-trans-permethrin-by-rat-and-human-liver-microsomes-liver-cytosol-and-plasma-preparations
#12
Laura Hedges, Susan Brown, Audrey Vardy, Edward Doyle, Miyoung Yoon, Thomas G Osimitz, Brian G Lake
The metabolism of deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in liver microsomes, liver cytosol and plasma from male Sprague-Dawley rats aged 15, 21 and 90 days and from adult humans. DLM and CPM were metabolised by rat hepatic microsomal cytochrome P450 (CYP) enzymes and to a lesser extent by microsomal and cytosolic carboxylesterase (CES) enzymes, whereas TPM was metabolised to a greater extent by CES enzymes. In human liver, DLM and TPM were mainly metabolised by CES enzymes, whereas CPM was metabolised by CYP and CES enzymes...
April 19, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29659319/disposition-of-tris-4-chlorophenyl-methanol-and-tris-4-chlorophenyl-methane-in-male-and-female-harlan-sprague-dawley-rats-and-b6c3f1-n-mice-following-oral-and-intravenous-administration
#13
Natasha Catlin, Suramya Waidyanatha, Sherry R Black, James Mathews, Rodney W Snyder, Purvi Patel, Scott Watson, Timothy R Fennell
1. Tris(4-chlorophenyl)methane (TCPME) and Tris(4-chlorophenyl)methanol (TCPMOH) have been detected in various biota and human tissues. 2. The current studies were undertaken to investigate the disposition and metabolism of TCPME and TCPMOH in rats and mice. 3. [14 C]TCPME was well absorbed (≥ 66%) in male rats and mice following a single oral administration of 1, 10, or 100 mg/kg. The excretion of [14 C]TCPME-derived radioactivity in urine (≤ 2.5%) and feces (≤18%) was low. The administered dose was retained in tissues (≥ 64%) with adipose containing the highest concentrations...
April 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29658375/pharmacokinetic-alterations-in-poloxamer-407-induced-hyperlipidemic-rats
#14
Unji Lee, Mi Hye Kwon, Hee Eun Kang
1. Plasma lipid profile abnormalities in hyperlipidemia can potentially alter the pharmacokinetics of a drug in a complex manner. To evaluate these pharmacokinetic alterations in hyperlipidemia and to determine the underlying mechanism(s), poloxamer 407-induced hyperlipidemic rats (HL rats), a well-established animal model of hyperlipidemia have been used. 2. In this review, we summarize findings on the pathophysiological and gene expression changes in drug-metabolizing enzymes and transporters in HL rats. We discuss pharmacokinetic changes in drugs metabolized primarily via hepatic cytochrome P450 (CYPs) in terms of alterations in hepatic intrinsic clearance (CL'int ), free fraction in plasma (fu ), and hepatic blood flow rate (QH ), depending on the hepatic excretion ratio, as well as drugs eliminated primarily by mechanisms other than hepatic CYPs...
April 16, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29648495/the-s-oxidation-referee-1-minor-comment-1-of-s-carboxymethyl-l-cysteine-in-hepatic-cytosolic-fractions-from-btbr-and-phenylketonuria-enu1-and-enu2-mice-referee-1minor-comment-2
#15
Glyn B Steventon, Stephen C Mitchell
1. Mice that were heterozygous dominant for the enu1 and enu2 mutation in PAH resulted in hepatic PAH assays for SCMC that had significantly increased calculated Km (wt/enu1, 1.84-2.12 fold increase and wt/enu2 a 2.75 fold increase in PAH assays). The heterozygous dominant phenotypes showed a significantly reduced catalytic turnover of SCMC (wt/enu1, 6.11 fold decrease and wt/enu2 an 11.25 fold decrease in calculated Vmax ). Finally, these phenotypes also had a significantly reduced clearance, CLE (wt/enu1, 13...
April 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29642738/rats-and-rabbits-as-pharmacokinetic-screening-tools-for-long-acting-intramuscular-depots-case-study-with-paliperidone-palmitate-suspension
#16
Harilal Patel, Prakash Patel, Nirav Modi, Pinakin Patel, Yogesh Wagh, Alex George, Nirmal Desai, Nuggehally R Srinivas
1. Development of prodrug of paliperidone (9-hydroxyrisperidone) long-acting intramuscular injection has enabled delivery over 4-week time period with improved compliance. 2. Key aim of work was to establish a reliable preclinical model which may potentially serve as a screening tool for judging the pharmacokinetics of paliperidone formulation(s) prior to human clinical work. 3. Sparse sampling composite study was used in rats, (Wistar/Sprague-Dawley (n = 10)). A serial blood sampling study design was used in rabbits (n = 4)...
April 12, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29629619/on-the-population-pharmacokinetics-and-the-enterohepatic-recirculation-of-total-ezetimibe
#17
K Soulele, V Karalis
1. Ezetimibe is a potent cholesterol absorption inhibitor, with an erratic pharmacokinetic (PK) profile, attributed to an extensive enterohepatic recirculation (EHC). 2. The aim of this study was to develop a population PK model able to adequately characterize the complex distribution processes of total ezetimibe. The analysis was performed on the individual concentration-time data obtained from 28 healthy subjects who participated in a bioequivalence study comparing two oral ezetimibe formulations. The population PK analysis was performed using nonlinear mixed effect modelling, where different EHC models were developed and evaluated for their performance...
April 9, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29619871/prediction-of-human-pharmacokinetics-of-typical-compounds-by-a-physiologically-based-method-using-chimeric-mice-with-humanized-liver
#18
Keigo Nakayama, Soichiro Ito, Masahiro Suzuki, Hiroaki Takubo, Hiroshi Yamazaki, Yukihiro Nomura
1. In this study, total body clearance (CLt ), volume of distribution at steady state (Vss ) and plasma concentration-time profiles in humans of model compounds were predicted using chimeric mice with humanized livers. 2. On the basis of assumption that unbound intrinsic clearance (CLUint ) per liver weight in chimeric mice was equal to those in humans, CLt were predicted by substituting human liver blood flow and liver weights in well-stirred model. Vss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SFKp ) in chimeric mice estimated from a difference between the observed and predicted Vss ...
April 5, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29543105/regioselectivity-significantly-impacts-microsomal-glucuronidation-efficiency-of-r-s-6-7-and-8-hydroxywarfarin
#19
So-Young Kim, Drew R Jones, Ji-Yeon Kang, Chul-Ho Yun, Grover P Miller
Coumadin (R/S-warfarin) metabolism plays a critical role in patient response to anticoagulant therapy. Several cytochrome P450s oxidize warfarin into R/S-6-, 7-, 8-, 10, and 4'-hydroxywarfarin that can undergo subsequent glucuronidation by UDP-glucuronosyltransferases (UGTs); however, current studies on recombinant UGTs cannot be adequately extrapolated to microsomal glucuronidation capacities for the liver. Herein, we estimated the capacity of the average human liver to glucuronidate hydroxywarfarin and identified UGTs responsible for those metabolic reactions through inhibitor phenotyping...
March 28, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29521134/effects-of-cyp3a4-1g-and-cyp3a5-3-polymorphisms-on-pharmacokinetics-of-tylerdipine-hydrochloride-in-healthy-chinese-subjects
#20
Sufeng Zhou, Mingxue Tao, Yuanyuan Wang, Lu Wang, Lijun Xie, Juan Chen, Yuqing Zhao, Yun Liu, Hongwen Zhang, Ning Ou, Guangji Wang, Feng Shao, Jiye Aa
The aim of this analysis was to explore the influence of CYP3A4*1G and CYP3A5*3 polymorphisms on the pharmacokinetics of tylerdipine in healthy Chinese subjects. A total of 64 and 63 healthy Chinese subjects were included and identified as the genotypes of CYP3A4*1G and CYP3A5*3, respectively. Plasma samples were collected for up to 120 h post-dose to characterize the pharmacokinetic profile following single oral dose of the drug (5, 15, 20, 25 and 30 mg). Plasma levels were measured by a high-performance liquid chromatography-mass spectrometry (LC-MS/MS)...
March 28, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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