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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/29444903/generation-and-characterization-of-a-cyp2c11-null-rat-model-by-using-the-crispr-cas9-method
#1
Yuan Wei, Li Yang, Xiaoyan Zhang, Danjuan Sui, Changsuo Wang, Kai Wang, Mangting Shan, Dayong Guo, Hongyu Wang
CYP2C11 is involved in the metabolism of many drugs in rats. To assess the roles of CYP2C11 in physiology and drug metabolism, a CYP2C11-null rat model was generated using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 method. A 2-bp insertion was added to exon 6 of CYP2C11 in Sprague-Dawley rats. CYP2C11 was not detected by Western blotting in liver microsomes of CYP2C11-null rats. No off-target effects were found at eleven predicted sites of the knockout model. The CYP2C11-null rats were viable and had no obvious abnormalities, with the exception of reduced fertility...
February 14, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29440179/role-of-c-jun-n-terminal-kinase-in-pregnane-x-receptor-mediated-induction-of-human-cytochrome-p4503a4-in-vitro
#2
Guncha Taneja, Chun Chu, Paramahamsa Maturu, Bhagavatula Moorthy, Romi Ghose
Cytochrome P450 (CYP) 3A4 is the most abundant drug metabolizing enzyme and is responsible for the metabolism of ~50% of clinically available drugs. Induction of CYP3A4 impacts the disposition of its substrates and leads to harmful clinical consequences such as failure of therapy. In order to prevent such undesirable consequences, molecular mechanisms of regulation of CYP3A4 need to be fully understood. CYP3A4 induction is primarily regulated by the xenobiotic nuclear receptor, pregnane-X-receptor (PXR). After ligand binding, PXR is transported to the nucleus, where it binds to the CYP3A4 promoter and induces its gene expression...
February 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29440178/evaluation-of-alteration-in-hepatic-and-intestinal-bcrp-function-in-vivo-due-to-abcg2-c-421c-a-polymorphism-based-on-pbpk-analysis-of-rosuvastatin
#3
Azusa Futatsugi, Kota Toshimoto, Takashi Yoshikado, Yuichi Sugiyama, Yukio Kato
Polymorphism c.421C>A in ABCG2 gene is thought to reduce the activity of breast cancer resistance protein (BCRP), a xenobiotic transporter, although it is not clear which organ(s) contributes to the polymorphism-associated pharmacokinetic change. The aim of the present study was to quantitatively estimate the influence of c.421C>A on intestinal and hepatic BCRP activity, using a physiologically based pharmacokinetic (PBPK) model of rosuvastatin developed from clinical data and several in vitro studies...
February 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29438977/posttranscriptional-regulation-of-ugt2b10-hepatic-expression-and-activity-by-alternative-splicing
#4
Adrien Labriet, Eric P Allain, Michele Rouleau, Yannick Audet-Delage, Lyne Villeneuve, Chantal Guillemette
The detoxification enzyme UDP-glucuronosyltransferase UGT2B10 is specialized in the N-linked glucuronidation of many drugs and xenobiotics. Preferred substrates possess tertiary aliphatic amines and heterocyclic amines such as tobacco carcinogens and several anti-depressants and anti-psychotics. We hypothesized that alternative splicing (AS) constitutes a mean to regulate steady state levels of UGT2B10 and enzyme activity. We established the transcriptome of UGT2B10 in normal and tumoral tissues of multiple individuals...
February 9, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29439129/simultaneous-assessment-in-vitro-of-transporter-and-metabolic-processes-in-hepatic-drug-clearance-use-of-a-media-loss-approach
#5
James Harrison, Tom De Bruyn, Adam S Darwich, J Brian Houston
Hepatocyte drug depletion-time assays are well established for the determination of metabolic clearance in vitro. The present study focuses on the refinement and evaluation of a "media loss" assay, an adaptation of the conventional depletion assay involving centrifugation of hepatocytes prior to sampling, allowing estimation of uptake in addition to metabolism. Using experimental procedures consistent with a high throughput, a selection of 12 compounds with a range of uptake and metabolism characteristics (atorvastatin, cerivastatin, clarithromycin, erythromycin, indinavir, pitavastatin, repaglinide, rosuvastatin, saquinavir and valsartan, together with two control compounds - midazolam and tolbutamide) were investigated in the presence and absence of the cytochrome P450 inhibitor 1-aminobenzotriazole and organic anion transporter protein inhibitor rifamycin SV...
February 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29439128/comparison-of-proteomic-quantification-approaches-for-hepatic-drug-transporters-multiplexed-global-quantitation-correlates-with-targeted-proteomic-quantitation
#6
Anna Vildhede, Chuong Nguyen, Brian K Erickson, Ryan C Kunz, Richard Jones, Emi Kimoto, Francis Bourbonais, A David Rodrigues, Manthena V Varma
Targeted protein quantification using liquid chromatography-tandem mass spectrometry with stable isotope labelled standards is recognized as the gold standard of practice for protein quantification. Such assays, however, can only cover a limited number of proteins and developing targeted methods for larger numbers of proteins require substantial investment. Alternatively, large-scale global proteomic experiments along with computational methods such as the "total protein approach" (TPA) have the potential to provide extensive protein quantification...
February 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29436390/identification-of-galeterone-and-abiraterone-as-inhibitors-of-dehydroepiandrosterone-sulfonation-catalyzed-by-human-hepatic-cytosol-sult2a1-sult2b1b-and-sult1e1
#7
Caleb K Y Yip, Sumit Bansal, Siew Ying Wong, Aik Jiang Lau
Galeterone and abiraterone acetate are anti-androgens developed for the treatment of metastatic castration-resistant prostate cancer. In the present study, we investigated the effect of these drugs on dehydroepiandrosterone (DHEA) sulfonation catalyzed by human liver and intestinal cytosols and human recombinant sulfotransferase enzymes (SULT2A1, SULT2B1b, and SULT2E1), and compared their effects to those of other anti-androgens (cyproterone acetate, spironolactone, and danazol). Each of these chemicals (10 μM) inhibited DHEA sulfonation catalyzed by human liver and intestinal cytosols...
February 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29437875/inter-individual-differences-in-the-expression-of-abc-and-slc-family-transporters-in-human-skin-dna-methylation-regulates-transcriptional-activity-of-the-human-abcc3-mrp3-gene
#8
Tomoki Takechi, Takeshi Hirota, Tatsuya Sakai, Natsumi Maeda, Daisuke Kobayashi, Ichiro Ieiri
The identification of drug transporters expressed in human skin and inter-individual differences in gene expression are important for understanding the role of drug transporters in human skin. In the present study, we evaluated the expression of ABC and SLC transporters using human skin tissues. In skin samples, ABCC3 was expressed at the highest levels, followed by SLCO3A1, SLC22A3, SLC16A7, ABCA2, ABCC1, and SLCO2B1. Among the quantitated transporters, ABCC3 accounted for 20.0% of the total mean transporter mRNA content...
February 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29437874/comparison-of-species-and-cell-type-differences-in-fraction-unbound-of-liver-tissues-hepatocytes-and-cell-lines
#9
Keith A Riccardi, Sangwoo Ryu, Jian Lin, Phillip Yates, David A Tess, Rui Li, Dhirender Singh, Brian R Holder, Brendon Kapinos, George Chang, Li Di
Fraction unbound (fu) of liver tissue, hepatocytes and other cell types is an essential parameter used to estimate unbound liver drug concentration and intracellular free drug concentration. Fu,liver and fu,cell are frequently measured in multiple species and cell types in drug discovery and development for various applications. A comparison study of 12 matrices for fu,liver and fu,cell of hepatocytes in five different species (mouse, rat, dog, monkey and human), as well as fu,cell of Huh7 and HEK-293 cell lines, was conducted for 22 structurally diverse compounds with the equilibrium dialysis method...
February 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29437873/brain-distribution-of-a-novel-mek-inhibitor-e6201-implications-in-the-treatment-of-melanoma-brain-metastases
#10
Gautham Gampa, Minjee Kim, Nicholas Cook-Rostie, Janice Laramy, Jann N Sarkaria, Linda Paradiso, Louis DePalatis, William F Elmquist
Clinically meaningful efficacy in the treatment of brain tumors, including melanoma brain metastases (MBM), requires selection of a potent inhibitor against a suitable target, and adequate drug distribution to target sites in the brain. Deregulated constitutive signaling of mitogen-activated protein kinase (MAPK) pathway has been frequently observed in melanoma, and MEK has been identified to be an important target. E6201 is a potent synthetic small molecule MEK inhibitor. The purpose of this study was to evaluate brain distribution of E6201, and examine the impact of active efflux transport at the BBB on the CNS exposure of E6201...
February 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29437872/mathematical-and-experimental-validation-of-flux-dialysis-method-an-improved-approach-to-measure-unbound-fraction-for-compounds-with-high-protein-binding-and-other-challenging-properties
#11
John Cory Kalvass, Colin Phipps, Gary J Jenkins, Patricia Stuart, Xiaomei Zhang, Lance Heinle, Marjoleen Jma Nijsen, Volker Fischer
A flux dialysis method to measure unbound fraction (fu) of compounds with high protein binding and other challenging properties was tested and validated. The method is based on the principle that the initial flux rate of a compound through a size-excluding dialysis membrane is proportional to the product of compound initial concentration, fu and unbound dialysis membrane permeability (Pmem). Therefore fu can be determined from initial concentration and flux rate, assuming membrane Pmem is known. Compound initial flux rates for 14 compounds were determined by dialyzing human plasma containing compound (donor side) versus compound-free plasma (receiver side) and measuring the rate of compound appearance into the receiver side...
February 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29386233/lc-ms-differential-analysis-for-fast-and-sensitive-determination-of-biotransformation-of-therapeutic-proteins
#12
Ming Yao, Bingming Chen, Weiping Zhao, John T Mehl, Lingjun Li, Mingshe Zhu
Therapeutic biologics have become a fast-growing segment within the pharmaceutical industry during the past three decades. Although the metabolism of biologics is more predictable than small molecule drugs, biotransformation can significantly affect the activity of biologics. Unfortunately, there are only a limited number of published studies on the biotransformation of biologics, most of which are focused on one or a few types of modification. In this study, an untargeted LC-MS based differential analysis approach was developed to rapidly and precisely determine the universal biotransformation profile of biologics with the assistance of bioinformatic tools...
January 31, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29386232/interindividual-regulation-of-the-bcrp-abcg2-transporter-in-term-human-placentas
#13
Kristin M Bircsak, Jamie E Moscovitz, Xia Wen, Faith Archer, Poi Yu Sofia Yuen, Moiz Mohammed, Naureen Memon, Barry I Weinberger, Laura M Saba, Anna M Vetrano, Lauren M Aleksunes
The breast cancer resistance protein (BCRP/ABCG2) is a maternally-facing efflux transporter that regulates the placental disposition of chemicals. Transcription factors and gene variants are important regulatory factors that influence transporter expression. Here, we sought to identify the genetic and transcriptional mechanisms underlying the interindividual expression of BCRP mRNA and protein across 137 term placentas from uncomplicated pregnancies. Placental expression of BCRP and regulatory transcription factor mRNAs was measured using multiplex branched DNA analysis...
January 31, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29363499/metabolic-profiling-of-the-novel-hif2%C3%AE-inhibitor-pt2385-in-vivo-and-in-vitro
#14
Cen Xie, Xiaoxia Gao, Dongxu Sun, Youbo Zhang, Kristopher W Krausz, Xuemei Qin, Frank Gonzalez
PT2385 is a first-in-class, selective small molecule inhibitor of hypoxia inducible factor-2α (HIF-2α) developed for the treatment of advanced clear cell renal cell carcinoma. Preclinical results demonstrated that PT2385 has potent anti-tumor efficacy in mouse xenograft models of kidney cancer. It also has activity toward metabolic disease in a mouse model. However, no metabolism data is currently publicly available. It is of great importance to characterize the metabolism of PT2385 and identify its effect on systemic homeostasis in mice...
January 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29363498/a-novel-in-vitro-experimental-system-for-the-evaluation-of-drug-metabolism-cofactor-supplemented-permeabilized-cryopreserved-human-hepatocytes-metmax%C3%A2-cryopreserved-human-hepatocytes
#15
Albert P Li, Ming-Chih David Ho, Kirsten Amaral, Carol Loretz
We report here a novel experimental system - MetMax™ cryopreserved human hepatocytes (MMHH), for in vitro drug metabolism studies. MMHH consist of cofactor-supplemented permeabilized cryopreserved human hepatocytes. The use procedures for MMHH are significantly simplified from that for conventional cryopreserved human hepatocytes (CCHH): 1. Storage at -80o C instead of in liquid nitrogen; 2. Usage directly after thawing without centrifugation and microscopic evaluation of cell density and viability and cell density adjustment...
January 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29358184/curcumin-as-an-in-vivo-selective-intestinal-breast-cancer-resistance-protein-inhibitor-in-cynomolgus-monkeys
#16
Tsuyoshi Karibe, Tomoki Imaoka, Koji Abe, Osamu Ando
To estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (BCRP), in vivo approaches in nonclinical settings are desired in drug development. Clinical observation has identified curcumin as a promising candidate for in vivo selectiveBCRP inhibition, in addition to several well-known inhibitors, such as lapatinib and pantoprazole. This study aimed to confirm the inhibitory efficacy of curcumin on gastrointestinal BCRP function in cynomolgus monkeys and to perform comparisons with lapatinib and pantoprazole...
January 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29352069/identification-of-ketene-reactive-intermediate-of-erlotinib-possibly-responsible-for-inactivation-of-p450-enzymes
#17
Huimin Zhao, Siyuan Li, Zixin Yang, Ying Peng, Xiaohui Chen, Jiang Zheng
Erlotinib (ELT), a tyrosine kinase inhibitor, is widely used for the treatment of non-small-cell lung cancer in clinic. Unfortunately, severe drug-induced liver injury and other adverse effects occurred during the treatment. Meanwhile, ELT has been reported to be a mechanism-based inactivator of CYPs 3A4 and 3A5. The objectives of this study were to identify ketene intermediate of ELT and investigate the association of the acetylenic bioactivation with the enzyme inactivation caused by ELT. A ketene intermediate was detected in human microsomal incubations of ELT, using 4-bromobenzylamine as a trapping agent...
January 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29352068/maternal-fetal-disposition-and-metabolism-of-retrorsine-in-pregnant-rats
#18
Xia Li, Xiaojing Yang, E Xiang, Jinyuan Luo, Shuaikai Qiu, Yan Fang, Li Zhang, Yu Guo, Jiang Zheng, Hui Wang
Pyrrolizidine alkaloids (PAs) are extensively synthesized by plants and are commonly present in herbs and foodstuffs, which exhibit hepatotoxicity requiring metabolic activation by cytochrome P450 (CYP) 3A to form the electrophilic metabolites-pyrrolic ester. PAs also cause embryo toxicity, but the metabolic profiles of PAs in fetus and placenta have been far from clear. In this study, we determined the basal metabolic activation of retrorsine (RTS) in rat maternal liver, placenta and fetal liver in vitro, and examined the fetal toxicity and bioactivation of RTS in vivo...
January 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29352067/sandwich-cultured-hepatocytes-for-mechanistic-understanding-of-hepatic-disposition-of-parent-drugs-and-metabolites-by-transporter-enzyme-interplay
#19
Norikazu Matsunaga, Yukina Fukuchi, Haruo Imawaka, Ikumi Tamai
Functional interplay between transporters and drug-metabolizing enzymes is currently one of the hottest topics in the field of drug metabolism and pharmacokinetics. Uptake transporter-enzyme interplay is important to determine intrinsic hepatic clearance based on the extended clearance concept. Enzyme-efflux transporter interplay, which includes both sinusoidal (basolateral) and canalicular efflux transporters, determines the fate of metabolites formed in the liver. As sandwich-cultured hepatocytes (SCHs) maintain metabolic activities and form a canalicular network, the whole interplay between uptake/efflux transporters and drug-metabolizing enzymes can be investigated simultaneously...
January 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29348125/metabolism-and-disposition-of-a-novel-selective-%C3%AE-7-neuronal-acetylcholine-receptor-agonist-abt-126-in-humans-characterization-of-the-major-roles-for-flavin-containing-monooxygenases-and-udp-glucuronosyl-transferase-1a4-and-2b10-in-catalysis
#20
Hong Liu, David M Stresser, Melissa J Michmerhuizen, XIaofeng Li, Ahmed A Othman, Aimee D Reed, Michael R Schrimpf, Jens Sydor, Anthony J Lee
Mass balance, metabolism and excretion of ABT-126, an α7 nAChRs agonist, were characterized in healthy male subjects (n=4) following a single 100 mg (100 μCi) oral dose. The total recovery of the administered radioactivity was 94.0% (±2.09%) with 81.5% (± 10.2%) in urine and 12.4% (± 9.3%) in feces. Metabolite profiling indicated that ABT-126 had been extensively metabolized with 6.6% of the dose remaining as unchanged parent drug in urine. Parent drug accounted for 12.2% of the administered radioactivity in feces...
January 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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