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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/30409838/berberine-directly-impacts-the-gut-microbiota-to-promote-intestinal-farnesoid-x-receptor-activation
#1
Yuan Tian, Jingwei Cai, Wei Gui, Robert G Nichols, Imhoi Koo, Jingtao Zhang, Mallappa Anitha, Andrew D Patterson
Intestinal bacteria play an important role in bile acid metabolism and in the regulation of multiple host metabolic pathways (e.g., lipid and glucose homeostasis) through modulation of intestinal farnesoid X receptor (FXR) activity. Here, we examined the effect of berberine (BBR), a natural plant alkaloid, on intestinal bacteria using in vitro and in vivo models. In vivo, the metabolomic response and changes in mouse intestinal bacterial communities treated with BBR (100 mg/kg) for 5 days were assessed using NMR- and mass spectrometry-based metabolomics coupled with multivariate data analysis...
November 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30409837/quantitation-of-lysosomal-trapping-of-basic-lipophilic-compounds-using-in-vitro-assays-and-in-silico-predictions-based-on-the-determination-of-the-full-ph-profile-of-the-endo-lysosomal-system-in-rat-hepatocytes
#2
Maximilian V Schmitt, Philip Lienau, Gert Fricker, Andreas Reichel
Lysosomal sequestration may affect the pharmacokinetics, efficacy and safety of new basic lipophilic drug candidates potentially impacting their intracellular concentrations and tissue distribution. It may also be involved in drug-drug interactions, drug resistance or phospholipidosis. Currently, however, there are no assays to evaluate the lysosomotropic behaviour of compounds in a setting fully meeting the needs of drug discovery. We have therefore integrated a set of methods to reliably rank order, quantify and calculate the extent of lysosomal sequestration in rat hepatocytes...
November 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30389730/characterization-of-the-in-vitro-inhibitory-potential-of-the-oligonucleotide-imetelstat-on-human-cytochrome-p450-enzymes-with-predictions-of-in-vivo-drug-drug-interactions
#3
Faraz Kazmi, Carlo Sensenhauser, Tony Greway
Imetelstat, a 13-base oligonucleotide (5'-TAGGGTTAGACAA-3') is a potent, investigational telomerase inhibitor in clinical development for the treatment of hematologic myeloid malignancies. Modifications to imetelstat oligonucleotide chemistry include a N3'--P5' thio-phosphoramidate backbone linkage to improve biological stability and the addition of a palmitoyl tail at the 5'-position to enhance cellular membrane permeability. Other oligonucleotides have been previously shown to have in vitro test-system dependent outcomes where potent P450 inhibition in human liver microsomes (HLM) is observed but such inhibition is not observed in cryopreserved human hepatocytes (CHH)...
November 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30389729/quantitative-analysis-of-ugt1a-and-ugt2b-mrna-expression-in-rat-liver-and-small-intestine-sex-and-strain-differences
#4
Takaya Kutsukake, Yoichi Furukawa, Kyoko Ondo, Saki Gotoh, Tatsuki Fukami, Miki Nakajima
UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation of numerous endogenous and exogenous compounds to facilitate their excretion from the body. Rats are most widely used in nonclinical studies. Information regarding UGT species differences between rats and humans would be helpful for understanding human pharmacokinetics. In this study, we determined the absolute mRNA expressions of Ugt isoforms in the livers and small intestines of male and female Sprague-Dawley, Fischer344 and Wistar rats. The sum of the mRNA levels of Ugt isoforms expressed in the liver was significantly (P < 0...
November 2, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30385458/a-novel-pathogenic-ugt1a1-variant-in-a-sudanese-child-with-type-i-crigler-najjar-syndrome
#5
Walaa Elfar, Erkka Jarvinen, Weizhen Ji, Johanna Mosorin, Annalisa G Sega, Alina C Iuga, Steven J Lobritto, Monica Konstantino, Albert Chan, Moshe Finel, Saquib A Lakhani
Uridine diphosphate glucuronosyltransferases (UGTs) are key enzymes responsible for the body's ability to process of a variety of endogenous and exogenous compounds. Significant gains in the understanding of UGT function have come from the analysis of variants seen in patients. We cared for a Sudanese child who presented with clinical features of Type I Crigler-Najjar syndrome (CN-I), namely severe unconjugated hyperbilirubinemia leading to liver transplantation. CN-I is an autosomal recessive disorder caused by damaging mutations in the gene for UGT1A1, the hepatic enzyme responsible for bilirubin conjugation in humans...
November 1, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30366901/oral-co-administration-of-fluconazole-with-tramadol-markedly-increases-plasma-and-urine-concentrations-of-tramadol-and-the-o-desmethyltramadol-metabolite-m1-in-healthy-dogs
#6
Tania E Perez Jimenez, Butch Kukanich, Hyun Joo, Katrina L Mealey, Tamara L Grubb, Stephen A Greene, Michael H Court
Tramadol is used frequently in the management of mild to moderate pain conditions in dogs. This use is controversial because multiple reports in treated dogs demonstrate very low plasma concentrations of O-desmethyltramadol (M1), the active metabolite. The objective of this study was to identify a drug that could be co-administered with tramadol to increase plasma M1 concentrations thereby enhancing analgesic efficacy. In vitro studies were initially conducted to identify a compound that inhibited tramadol metabolism to N-desmethyltramadol (M2) and M1 metabolism to N,O didesmethyltramadol (M5) without reducing tramadol metabolism to M1...
October 26, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30348903/mechanistic-in-vitro-studies-indicate-that-the-clinical-drug-drug-interaction-between-telithromycin-and-simvastatin-acid-is-driven-by-time-dependent-inhibition-of-cyp3a4-with-minimal-effect-on-oatp1b1
#7
Robert Elsby, Victoria Hare, Hannah Neal, Samuel Outteridge, Catherine Pearson, Katie Plant, Rachel Upcott Gill, Philip Butler, Robert J Riley
A previous attempt to accurately quantify the increased simvastatin acid exposure due to drug-drug interaction (DDI) with coadministered telithromycin, using a mechanistic static model, substantially underpredicted the magnitude of area under the plasma concentration-time curve ratio (AUCR) based on reversible inhibition of cytochrome P450 (CYP) 3A4 and organic anion transporting polypeptide (OATP) 1B1 (Elsby et al., 2012). In order to reconcile this disconnect between predicted and clinically observed AUCR, telithromycin was evaluated as a time-dependent inhibitor of CYP3A4 in vitro , as well as an inhibitor of OATP1B1...
October 22, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30337443/evaluation-of-carbazeran-4-oxidation-and-o6-benzylguanine-8-oxidation-as-catalytic-markers-of-human-aldehyde-oxidase-impact-of-cytosolic-contamination-of-liver-microsomes
#8
Jiarong Xie, Nur Fazilah Saburulla, Shiyan Chen, Siew Ying Wong, Ze Ping Yap, Linghua Harris Zhang, Aik Jiang Lau
The current study investigated the contribution of microsomal cytochrome P450 and cytosolic aldehyde oxidase-1 (AOX-1) to carbazeran 4-oxidation and O6-benzylguanine 8-oxidation in human liver microsomal, cytosolic, and S9 fractions. Incubations containing carbazeran and human liver microsomes with or without exogenously added NADPH yielded comparable levels of 4-oxo-carbazeran. O6-Benzylguanine 8-oxidation occurred in microsomal incubations, and the extent was increased by NADPH. Human recombinant CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 did not catalyze carbazeran 4-oxidation, whereas CYP1A2 was highly active in O6-benzylguanine 8-oxidation...
October 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30275119/regional-differences-in-intestinal-drug-metabolism
#9
Raditya Iswandana, Marina Ika Irianti, Dorenda Oosterhuis, Hendrik S Hofker, Marjolijn T Merema, Marina H de Jager, Henricus Am Mutsaers, Peter Olinga
The intestines are key for the absorption of nutrients and water as well as drug metabolism, and it is well known that there are clear differences in the expression profile of drug metabolism enzymes along the intestinal tract. Yet, only a few studies have thoroughly investigated regional differences in human intestinal drug metabolism. In this study, we evaluated phase I and phase II metabolism in matched human ileum and colon precision-cut intestinal slices (PCIS). To this end, human PCIS were incubated for 3 h with testosterone (TT) and 7-hydroxycoumarin (7-HC) to examine phase I and phase II metabolism, respectively...
October 1, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30266733/polymorphisms-of-the-multidrug-pump-abcg2-a-systematic-review-of-their-effect-on-protein-expression-function-and-drug-pharmacokinetics
#10
Niall Heyes, Parth Kapoor, Ian D Kerr
The widespread expression and polyspecificity of the multidrug ABCG2 efflux transporter make it an important determinant of the pharmacokinetics of a variety of substrate drugs. Null ABCG2 expression has been linked to the Junior blood group. Polymorphisms affecting the expression or function of ABCG2 may have clinically important roles in drug disposition and efficacy. The most well studied SNP, Q141K (421C>A), is shown to decrease ABCG2 expression and activity, resulting in increased total drug exposure and decreased resistance to various substrates...
September 28, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30257855/identification-and-quantification-of-novel-major-metabolites-of-the-steroidal-aromatase-inhibitor-exemestane
#11
Shaman Luo, Gang Chen, Cristina I Truica, Cynthia C Baird, Zuping Xia, Philip Lazarus
Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of estrogen receptor-positive breast cancer. Although the known major metabolic pathway for EXE is reduction to form the active 17β-dihydro-EXE (17β-DHE) and subsequent glucuronidation to 17β-hydroxy-EXE-17-O-β;-D-glucuronide (17β-DHE-Gluc), previous studies suggest that other major metabolites exist for exemestane. In the present study, a liquid chromatography-mass spectrometry (LC-MS) approach was used to acquire accurate mass data in MSE mode, in which precursor ion and fragment ion data was obtained simultaneously to screen novel phase II EXE metabolites in urine specimens from women taking EXE...
September 26, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30232177/towards-a-combinatorial-approach-for-the-prediction-of-immunoglobulin-g-half-life-and-clearance
#12
Dennis R Goulet, Michael J Watson, Susan H Tam, Adam Zwolak, Mark L Chiu, William M Atkins, Abhinav Nath
The serum half-life and clearance of therapeutic monoclonal antibodies (mAbs) are critical factors that impact their efficacy and optimal dosing regimen. The pH-dependent binding of a mAb to the neonatal Fc receptor (FcRn) has long been recognized as an important determinant of its pharmacokinetics. However, FcRn affinity alone is not a reliable predictor of mAb half-life, suggesting that other biological or biophysical mechanisms must be accounted for. mAb thermal stability, which reflects its unfolding and aggregation propensities, may also relate to its pharmacokinetic properties...
September 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30232176/calcitriol-and-calcipotriol-modulate-transport-activity-of-abc-transporters-and-exhibit-selective-cytotoxicity-in-mrp1-overexpressing-cells
#13
Kee Wee Tan, Angelina Sampson, Bremansu Osa-Andrews, Surtaj Hussain Iram
Efflux transporters P-glycoprotein (P-gp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) can affect the efficacy and toxicity of a wide variety of drugs and are implicated in multidrug resistance (MDR). Eight test compounds, recently identified from an intramolecular FRET-based high throughput screening, were characterized for their interaction with MRP1. We report that the active metabolite of vitamin D3, calcitriol, and its analog calcipotriol are selectively cytotoxic to MRP1-overexpressing cells, besides inhibiting transport function of P-gp, MRP1, and BCRP...
September 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/30209037/metabolism-of-c-met-kinase-inhibitors-containing-quinoline-by-aldehyde-oxidase-electron-donating-and-steric-hindrance-effect
#14
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
#15
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/30171161/biotransformation-of-finerenone-a-novel-nonsteroidal-mineralocorticoid-receptor-antagonist-in-dogs-rats-and-humans-in-vivo-and-in-vitro
#16
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
#17
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/30158250/effect-of-celecoxib-on-differentiation-of-human-induced-pluripotent-stem-cells-into-hepatocytes-involves-stat5-activation
#18
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
#19
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
#20
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
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