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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/30209037/metabolism-of-c-met-kinase-inhibitors-containing-quinoline-by-aldehyde-oxidase-electron-donating-and-steric-hindrance-effect
#1
Jiang Wei Zhang, Wen Xiao, Zhen Ting Gao, Zheng Tian Yu, Ji Yue Jeff Zhang
Some quinoline containing c-Met kinase inhibitors are aldehyde oxidase (AO) substrates. 3-substituted quinoline triazolopyridine analogues were synthesized to understand the electron donating and steric hindrance effect on AO-mediated metabolism. Metabolic stability studies for these quinoline analogues were carried out in liver cytosol from mice, rats, cyno monkeys, and humans. Several 3-N-substituted analogues were found to be unstable in monkey liver cytosolic incubations (t1/2 < 10 min), and five of them (63, 53, 51, 11, and 71) were chosen for additional mechanistic studies...
September 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30194276/6-chloro-5-4-1-hydroxycyclobutyl-phenyl-1h-indole-3-carboxylic-acid-pf-06409577-is-a-highly-selective-substrate-for-glucuronidation-by-uridine-diphosphoglucuronosyl-transferase-ugt-1a1-relative-to-b-estradiol
#2
Kimberly Lapham, Jian Lin, Jonathan Novak, Christine Orozco, Mark Niosi, Li Di, Theunis C Goosen, Sangwoo Ryu, Keith Riccardi, Heather Eng, Kimberly O Cameron, Amit S Kalgutkar
6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid (PF-06409577) is a direct activator of the human β1-containing adenosine monophosphate-activated protein kinase (AMPK)isoforms. The clearance mechanism of PF-06409577 in animals and humans involves uridine diphosphoglucuronosyl transferase (UGT)-mediated glucuronidation to an acyl glucuronide metabolite M1, which retains selective activation of human 1-containing AMPK isoforms. This manuscript describes a detailed characterization of the human UGT isoform(s) responsible for glucuronidation of PF-06409577 to M1...
September 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30171163/human-pluripotent-stem-cell-derived-kidney-model-for-nephrotoxicity-studies
#3
Piyush Bajaj, A David Rodrigues, Claire M Steppan, Sandra J Engle, Sumathy Mathialagan, Thomas Schroeter
Current in vitro models for identifying nephrotoxins are poorly predictive. Human pluripotent stem cells (hPSCs) were differentiated into three dimensional, multicellular structures containing proximal tubule cells (PTCs) and podocytes and evaluated as a platform for predicting nephrotoxicity. PTCs showed megalin-dependent, cubilin-mediated endocytosis of fluorescently labeled dextran and active gamma-glutamyl transpeptidase enzymes. Transporters from both the ABC and the SLC families were present at physiological levels in the differentiated cells, however, important renal transporters such as OAT1, OAT3, and OCT2 were present only at lower levels...
August 31, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30171162/porcine-prediction-of-pharmacokinetic-parameters-in-people-a-pig-in-a-poke
#4
Huadong Tang, Michael Mayersohn
The minipig has become an animal of considerable interest in preclinical drug development. It has been used in toxicology research and in examining/establishing regulatory guidelines as a non-rodent animal model. We have reviewed some basic issues that one would want to consider in the development and testing of any animal model for humans. The pig is a reasonable alternative to the dog, but there are some clear limitations and unexplained disparities in the literature, which require further study, primary among these is the need for standardization in choice of breed and sex and routine protocols...
August 31, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30171161/biotransformation-of-finerenone-a-novel-nonsteroidal-mineralocorticoid-receptor-antagonist-in-dogs-rats-and-humans-in-vivo-and-in-vitro
#5
Michael Gerisch, Roland Heinig, Anna Engelen, Dieter Lang, Peter Kolkhof, Martin Radtke, Johannes Platzek, Kai Lovis, Gabriele Rohde, Thomas Schwarz
Mass balance and biotransformation of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, were investigated in four healthy male volunteers following a single oral administration of 10 mg (78 µCi) of [14C]finerenone and compared with data from studies in dogs and rats. The total recovery of the administered radioactivity was 101% in humans, 94.7% in dogs, and 95.2% in rats. In humans, radioactivity was mainly excreted renally (80%); in rats, it was primarily the biliary/fecal route (76%); and in dogs, excretion was more balanced...
August 31, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30166405/relationship-between-in-vivo-cyp3a4-activity-cyp3a5-genotype-and-systemic-tacrolimus-metabolite-parent-drug-ratio-in-renal-transplant-recipients-and-healthy-volunteers
#6
Thomas Vanhove, Hylke de Jonge, Henriette de Loor, Marlies Oorts, Jan de Hoon, Anton Pohanka, Pieter Annaert, Dirk Rj Kuypers
CYP3A5 genotype is a major determinant of tacrolimus clearance, and has been shown to affect systemic tacrolimus metabolite/parent ratios in healthy volunteers, which may have implications for efficacy and toxicity. In a cohort of 50 renal transplant recipients who underwent quantification of CYP3A4 activity using the oral midazolam drug probe, we confirmed that CYP3A5 genotype is the single most important determinant of tacrolimus metabolite/parent ratio (CYP3A5 expressors displayed 2.7- and 2-fold higher relative exposure to 13-desmethyltacrolimus [DMT] and 31-DMT, respectively, P<0...
August 30, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30166404/gene-by-environment-interaction-of-bcrp-and-mcd-diet-induced-nonalcoholic-steatohepatitis-alters-sn-38-disposition
#7
Erica L Toth, Hui Li, Anika L Dzierlenga, John D Clarke, Anna Vildhede, Michael Goedken, Nathan J Cherrington
Disease progression to nonalcoholic steatohepatitis (NASH) has profound effects on the expression and function of drug metabolizing enzymes and transporters, which provides a mechanistic basis for variable drug response. Breast cancer resistance protein (BCRP), a biliary efflux transporter, exhibits increased liver mRNA expression in NASH patients and preclinical NASH models, but the impact on function is unknown. It was shown that the transport capacity of multidrug resistance protein 2 (MRP2) is decreased in NASH...
August 30, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30158250/effect-of-celecoxib-on-differentiation-of-human-induced-pluripotent-stem-cells-into-hepatocytes-involves-stat5-activation
#8
Hiroki Okumura, Anna Nakanishi, Tadahiro Hashita, Takahiro Iwao, Tamihide Matsunaga
The liver abundantly expresses various drug-metabolizing enzymes and, thus, plays a central role in drug metabolism. In this regard, cytochrome P450 (CYP) 3A4 is one of the most important enzymes in the liver. Therefore, in drug development, CYP3A4 metabolism in the liver is important for predicting pharmacokinetics. Human induced pluripotent stem cell-derived hepatocytes (hiHep) have become a major focus as models of drug metabolism in drug development studies. However, drug metabolic activities, such as those involving CYP3A4, are lower in hiHep than in human primary hepatocytes...
August 29, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30158249/an-ex-vivo-fermentation-screening-platform-to-study-drug-metabolism-by-human-gut-microbiota
#9
Evita van de Steeg, Frank H J Schuren, R Scott Obach, Claire van Woudenbergh, Gregory S Walker, Margreet Heerikhuisen, Irene H G Nooijen, Wouter H J Vaes
Colon microbiota-based drug metabolism has received little attention thus far in the process of drug development, whereas the role of gut microbiota in clinical safety and efficacy of drugs has become more clear. Many of these studies have been performed using animal studies, but the translational value of these data with respect to drug pharmacokinetics, efficacy, and safety is largely unknown. To investigate human colon microbiota-mediated drug metabolism, we applied a recently developed ex vivo fermentation screening platform, in which human colonic microbiota conditions are simulated...
August 29, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30154106/evaluation-of-organic-anion-transporter-1a2-knockin-mice-as-a-model-of-human-blood-brain-barrier
#10
Yamato Sano, Tadahaya Mizuno, Tatsuki Mochizuki, Yasuno Uchida, Mina Umetsu, Tetsuya Terasaki, Hiroyuki Kusuhara
The present study aimed to establish a humanized mouse model with which to explore OATP1A2-mediated transcellular transport of drug substrates across the blood - brain barrier (BBB), and to evaluate the usefulness of the humanized mice in preclinical studies. Sulpiride, amisulpride, sultopride, and triptans were used as probes to discriminate OATP1A2 and Oatp1a4. We generated a mouse line humanized for OATP1A2 by introducing the coding region downstream of the Oatp1a4 promoter using the CRISPR/Cas9 technique...
August 28, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30154105/health-relevant-phenotypes-in-the-offspring-of-mice-given-car-activators-prior-to-pregnancy
#11
Karin Dietrich, Jan Baumgart, Leonid Eshkind, Lea Reuter, Ute Godtel-Armbrust, Elke Butt, Michael Musheev, Federico Marini, Piyush More, Tanja Grosser, Christof Niehrs, Leszek Wojnowski, Marianne Mathas
The hepatic induction in response to drugs and environmental chemicals affects drug therapies and energy metabolism. We investigated whether the induction is transmitted to the offspring. We injected 3-day and 6-week-old F0 female mice with the activator of the nuclear receptor CAR (constitutive androstane receptor, NR1I3) TCPOBOP and mated them 1-6 weeks afterwards. We detected in the offspring long-lasting alterations of CAR-mediated drug disposition, energy metabolism, and lipid profile. The transmission to F1 was mediated by TCPOBOP transfer from the F0 adipose tissue via milk, as revealed by embryo transfer, cross-fostering experiments, and liquid chromatography-mass spectrometry analyses...
August 28, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30154104/circadian-regulation-of-hepatic-cytochrome-p450-2a5-by-peroxisome-proliferator-activated-receptor-gamma
#12
Jiangming Deng, Lianxia Guo, Baojian Wu
Human CYP2A6 (mouse Cyp2a5) plays an important role in metabolism and detoxification of various drugs and chemicals. Here, we investigate a potential role of peroxisome proliferator-activated receptor gamma (Ppar-γ) in circadian regulation of Cyp2a5 enzyme. We first showed that Cyp2a5 mRNA and protein in mouse liver displayed robust circadian oscillations. Consistent with circadian protein pattern, Cyp2a5-mediated 7-hydroxylation of coumarin was circadian-time dependent. Formation of 7-hydroxycoumarin was more extensive at the dosing-time of ZT2 than ZT14...
August 28, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30135246/perspective-on-the-application-of-microphysiological-systems-to-drug-transporter-studies
#13
Pedro Caetano-Pinto, Simone H Stahl
Transmembrane flux of a drug within a tissue or organ frequently involves a complex system of transporters from multiple families that have redundant and overlapping specificities. Current in vitro systems poorly represent physiology, with reduced expression and activity of drug transporter proteins, therefore, novel models that recapitulate the complexity and interplay among various transporters are needed. The development of microphysiological systems that bring simulated physiological conditions to in vitro cell culture models have enormous potential to better reproduce the morphology and transport activity across several organ models especially in tissues like the liver, kidney, intestine or the blood-brain-barrier where drug transporters play a key role...
August 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30135245/advances-in-engineered-human-liver-platforms-for-drug-metabolism-studies
#14
Gregory H Underhill, Salman R Khetani
Metabolism in the liver often determines the overall clearance rates of many pharmaceuticals. Furthermore, induction or inhibition of the liver's drug metabolism enzymes by perpetrator drugs can influence the metabolism of victim drugs (drug-drug interactions). Therefore, determining liver-drug interactions is critical during preclinical drug development. Unfortunately, studies in animals are often of limited value due to significant differences in liver's metabolic pathways across different species. To mitigate such limitations, the pharmaceutical industry employs a continuum of human liver models, ranging from microsomes, transfected cell lines, and cultures of primary human hepatocytes (PHH)...
August 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30135244/assessment-of-the-biotransformation-of-low-turnover-drugs-in-the-h%C3%AE-rel-human-hepatocyte-coculture-model
#15
Richard D Burton, Todd Hieronymus, Taysir Chamem, David Heim, Shelby Anderson, Xiaochun Zhu, J Matthew Hutzler
Metabolic profiles of four drugs possessing diverse metabolic pathways (timolol, meloxicam, linezolid, and XK469) were compared following incubations in both suspended cryopreserved human hepatocytes and the HμREL hepatocyte coculture model. In general, minimal metabolism was observed following 4 hour incubations in both suspended hepatocytes and the HμREL model, whereas incubations conducted up to 7 days in the HμREL coculture model resulted in more robust metabolic turnover. In the case of timolol, in vivo human data suggests that 22% of the dose is transformed via multi-step oxidative opening of the morpholine moiety...
August 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30135243/a-commentary-finding-tmax-and-cmax-in-multi-compartmental-models
#16
Yi Rang Han, Ping I Lee, K Sandy Pang
Drug absorption data are critical in bioequivalence comparisons, and factors such as the maximum concentration (Cmax ), the time to achieve Cmax (or Tmax ), as well as the area under the curve (AUC) are important metrics. It is generally accepted that the AUC is a meaningful estimate of the extent of absorption and Tmax or Cmax may be used for assessing the rate of absorption. But the estimation of the rate of absorption with Tmax or Cmax is not always feasible, as explicit solutions relating Tmax and Cmax to the absorption (ka ) and elimination rate (k) constants exist only for the one and not multi-compartment oral model...
August 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30135242/application-of-intestinal-epithelial-cells-differentiated-from-human-induced-pluripotent-stem-cells-for-studies-of-prodrug-hydrolysis-and-drug-absorption-in-the-small-intestine
#17
Takanori Akazawa, Shinpei Yoshida, Shuichi Ohnishi, Takushi Kanazu, Makoto Kawai, Koji Takahashi
Cell models to investigate intestinal absorption functions, such as of transporters and metabolic enzymes, are essential for oral drug discovery and development. The purpose of this study was to generate intestinal epithelial cells from human induced pluripotent stem cells (hiPSC-IECs) and then clarify whether the functions of hydrolase and transporters in them reflect oral drug absorption in the small intestine. The hiPSC-IECs showed the transport activities of P-gp, BCRP, and PEPT1, revealed by using their probe substrates ([3 H]digoxin, sulfasalazine, and [14 C]glycylsarcosine), and the metabolic activities of CYP3A4, CES2, and CES1, which were clarified using their probe substrates (midazolam, irinotecan, and temocapril)...
August 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30135241/accurate-estimation-of-in-vivo-inhibition-constants-of-inhibitors-and-fraction-metabolized-of-substrates-with-physiologically-based-pharmacokinetic-drug-drug-interaction-models-incorporating-parent-drugs-and-metabolites-of-substrates-with-cluster-newton-method
#18
Kenta Yoshida, Kazuya Maeda, Akihiko Konagaya, Hiroyuki Kusuhara
Accurate estimation of "in vivo" inhibition constants (Ki) of inhibitors and fraction metabolized (fm) of substrates is of high importance for drug-drug interaction (DDI) prediction based on physiologically-based pharmacokinetic (PBPK) models. We hypothesized that analysis of the pharmacokinetic alterations of substrate metabolites in addition to parent drug would enable accurate estimation of in vivo Ki and fm. Twenty four pharmacokinetic DDIs caused by CYP inhibition were analyzed with PBPK models using an emerging parameter estimation method, Cluster Newton Method, which enables efficient estimation of a large number of parameters to describe pharmacokinetics of parent and metabolized drugs...
August 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30126863/crispr-cas9-a-new-addition-to-the-drug-metabolism-and-disposition-tool-box
#19
Maria Karlgren, Ivailo Simoff, Markus Keiser, Stefan Oswald, Per Artursson
Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein 9 or CRISPR-Cas9 has been extensively used as a gene-editing technology during recent years. Unlike earlier technologies for gene-editing or gene knockdown, such as zinc finger nucleases and RNAi, CRISPR-Cas9 is comparably easy to use, affordable and versatile. Recently CRISPR-Cas9 has been applied in studies of drug absorption, disposition, metabolism and excretion (ADME) and for ADME model generation. Today about 50 papers have been published describing in vitro or in vivo CRISPR-Cas9 gene-editing of ADME and ADME-related genes...
August 20, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30126862/physiologically-relevant-humanized-intestinal-systems-to-study-metabolism-and-transport-of-small-molecule-therapeutics-mini-review
#20
Aarti Sawant-Basak, A David Rodrigues, Matthew Lech, Regis Doyonnas, Marion Kasaian, Bhagwat Prasad, Nikolaos Tsamandouras
Intestinal disposition of small molecules involves interplay of drug-metabolizing enzymes, transporters, and host-microbiome, which has spurred the development of in vitro intestinal models derived from primary tissue sources. Such models have been bio-engineered from intestinal crypts, mucosal extracts, iPSC-derived organoids, and human intestinal tissue. The present mini-review discusses the utility and limitations of these human derived models in support of small molecule drug metabolism and disposition...
August 20, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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