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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/28821485/simple-evaluation-method-for-cyp3a4-induction-from-human-hepatocytes-the-relative-factor-approach-with-an-induction-detection-limit-concentration-based-on-the-emax-model
#1
Shino Kuramoto, Motohiro Kato, Hidetoshi Shindoh, Akihisa Kaneko, Masaki Ishigai, Seiji Miyauchi
We investigated the robustness and utility of the relative factor (RF) approach based on the Emax model, which was reported by Kaneko, using mRNA induction data of 10 typical CYP3A4 inducers in cryopreserved human hepatocytes. The RF value is designated as the ratio of the induction detection limit concentration (IDLC) for a standard inducer, such as rifampicin (RIF) or phenobarbital (PB), to that for the compound (RFRIF is IDLCRIF/IDLCcpd; RFPB is IDLCPB/IDLCcpd). An important feature of the RF approach is that the profiles of the induction response curves on the logarithmic scale remain unchanged irrespective of inducers but are shifted parallel depending on the EC50 values...
August 18, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28821484/measurement-and-mathematical-characterization-of-cell-level-pharmacokinetics-of-antibody-drug-conjugates-a-case-study-with-trastuzumab-vc-mmae
#2
Aman P Singh, Dhaval K Shah
The main objective of this work was to understand and mathematically characterize the cellular disposition of a tool ADC, trastuzumab-vc-MMAE (T-vc-MMAE). Towards this goal, three different analytical methods were developed to measure the concentrations of different ADC related analytes in the media and cell lysate. An LC-MS/MS method was developed to quantify unconjugated drug (i.e. MMAE) concentrations, a forced deconjugation method was developed to quantify total drug concentrations, and an ELISA method was developed to quantify total antibody (i...
August 18, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28790147/hepatocyte-specific-deletion-of-egfr-in-mice-reduces-hepatic-abcg2-transport-activity-measured-with-11-c-erlotinib-and-positron-emission-tomography
#3
Alexander Traxl, Karin Komposch, Elisabeth Glitzner, Thomas Wanek, Severin Mairinger, Oliver Langer, Maria Sibilia
The epidermal growth factor receptor (EGFR) regulates cellular expression levels of breast cancer resistance protein (humans: ABCG2, rodents: Abcg2) via its downstream signaling pathways. Drugs that inhibit EGFR signaling (e.g. tyrosine kinase inhibitors, antibodies) may lead to ABCG2-mediated drug-drug interactions (DDIs) by changing disposition of concomitantly administered ABCG2 substrate drugs. In this study we used positron emission tomography (PET)/magnetic resonance (MR) imaging to compare disposition of the model Abcg2 substrate [(11)C]erlotinib in a mouse model of hepatocyte-specific deletion of EGFR (EGFR(Δhep) mice, n = 5) with EGFR(fl/fl) control mice (n = 6), which have normal EGFR expression levels in all tissues...
August 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28790146/cyp1a1-mediated-intramolecular-rearrangement-of-aminoazepane-in-gdc-0339
#4
Ryan H Takahashi, Xiaojing Wang, Nathaniel L Segraves, Jing Wang, Jae H Chang, Siamak Cyrus Khojasteh, Shuguang Ma
GDC-0339 is a novel small molecule pan-Pim kinase inhibitor that was discovered as a potential treatment for multiple myeloma. During the in vitro and in vivo metabolite profiling of GDC-0339, a metabolite was detected that had the same elemental composition as the parent but was distinct based on chromatographic separation and mass spectrometric fragmentation pattern. High resolution MS/MS data indicated the metabolite was modified at the aminoazepane moiety. The structure was solved by NMR analysis of the isolated metabolite and further confirmed by comparing it to a synthetic standard...
August 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28784689/an-investigation-into-the-prediction-of-in-vivo-clearance-for-a-range-of-flavin-containing-monooxygenase-substrates
#5
Barry C Jones, Abhishek Srivastava, Nicola Colclough, Joanne Wilson, Venkatesh Pilla Reddy, Sara Amberntsson, Danxi Li
Flavin-containing monooxygenases (FMO) are metabolic enzymes mediating the oxidation of nucleophilic atoms such as nitrogen, sulfur, phosphorus and selenium. The enzymes share similar properties to the cytochrome P450 system but can be differentiated through lability to heat and selective inhibition by methimazole. This study investigated 10 compounds with varying degrees of FMO involvement to determine the nature of the correlation between human in-vitro and in-vivo unbound intrinsic clearance. In order to confirm and quantify the extent of FMO involvement 6 of the compounds were investigated in human liver microsomal (HLM) in-vitro assays with heat deactivation and methimazole inhibition...
August 7, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28778997/involvement-of-nf-%C3%AE%C2%BAb-not-pxr-in-inflammation-mediated-regulation-of-hepatic-transporters
#6
Walaa A Abualsunun, Micheline Piquette-Miller
Endotoxin-induced inflammation decreases the hepatic expression of several drug transporters, metabolizing enzymes and nuclear transcription factors including PXR. As the nuclear factor NF-κB is a major mediator of inflammation, and reciprocal repression between NF-κB and PXR signaling has been reported, the objective of this study was to examine whether NF-κB directly regulates the expression of transporters or exerts its effect indirectly via PXR. PXR deficient (-/-) or wild-type (+/+) male mice were dosed with the selective NF-κB inhibitor PHA408 (40 mg/kg ip) or vehicle (n=5-8/group) followed by endotoxin (5 mg/kg) or saline 30 minutes later...
August 4, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28768682/quantitative-characterization-of-major-hepatic-udp-glucuronosyltransferase-ugt-enzymes-in-human-liver-microsomes-comparison-of-two-proteomic-methods-and-correlation-with-catalytic-activity
#7
Brahim Achour, Alyssa Dantonio, Mark Niosi, Jonathan J Novak, John K Fallon, Jill Barber, Philip C Smith, Amin Rostami-Hodjegan, Theunis C Goosen
Quantitative characterization of UDP-glucuronosyltransferase (UGT) enzymes is valuable in glucuronidation reaction phenotyping, predicting metabolic clearance and drug-drug interactions using extrapolation exercises based on pharmacokinetic modeling. Different quantitative proteomic workflows have been employed to quantify UGT enzymes in various systems, with reports indicating large variability in expression, which cannot be explained by inter-individual variability alone. To evaluate the effect of methodological differences on end-point UGT abundance quantification, eight UGT enzymes were quantified in 24 matched liver microsomal samples by two laboratories using stable isotope-labeled (SIL) peptides or quantitative concatemer (QconCAT) standard, and measurements were assessed against catalytic activity in seven enzymes (n=59)...
August 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28760731/differential-nitric-oxide-derived-protein-modifications-of-flavin-containing-monooxygenases-in-type-1-allergic-mice
#8
Tadatoshi Tanino, Toru Bando, Akira Komada, Yukie Nojiri, Yuna Okada, Yukari Ueda, Eiichi Sakurai
Flavin-containing monooxygenases (FMOs) are major mammalian non-cytochrome P450 oxidative enzymes. T Helper2 cell-activated allergic diseases produce excess levels of nitric oxide (NO) that modify the functions of proteins. However, it remains unclear whether allergy-induced NO affects the pharmacokinetics of drugs metabolized by FMOs. This study investigated alterations of hepatic microsomal FMO1 and FMO3 activities in type 1 allergic mice, and further examined the interaction of FMO1 and FMO3 with allergy-induced NO...
July 31, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28716828/creation-and-preliminary-characterization-of-pregnane-x-receptor-and-constitutive-androstane-receptor-knockout-rats
#9
Kevin P Forbes, Evguenia Kouranova, Daniel Tinker, Karen Janowski, Doug Cortner, Aaron McCoy, Xiaoxia Cui
The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of Phase I (Cytochrome P450s), Phase II metabolizing enzymes and transporter genes in response to stimulation from xenobiotics, including prescription drugs. PXR and CAR are also involved in other endogenous processes, such as in inflammation, glucose homeostasis and lipid metabolism, and are thus potential drug targets themselves. PXR and CAR knockout and humanized mouse models have proven useful...
July 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28698304/prediction-of-clinically-relevant-herb-drug-clearance-interactions-using-a-whole-cell-approach-schisandra-sphenanthera-case-study
#10
Jonathan P Jackson, Kimberly M Freeman, Weslyn W Friley, Ashley G Herman, Christopher B Black, Kenneth R Brouwer, Amy L Roe
The Schisandraceae family is reported to have a range of pharmacological activities, including anti-inflammatory effects. As with all herbal preparations, extracts of Schisandra species are mixtures composed of >50 lignans including schizandrins and deoxyschizandrins. In China, Schisandra sphenanthera extract (SSE) is often co-administered with immunosuppressant treatment of transplant recipients. In cases of co-administration, the potential for herb-drug interactions (HDI) increases. Clinical studies have been employed to assess HDI of extracts including SSE...
July 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28698303/evaluation-of-expression-and-glycosylation-status-of-ugt1a10-in-supersomes-and-intestinal-epithelial-cells-with-a-novel-specific-ugt1a10-monoclonal-antibody
#11
Shingo Oda, Yukiko Kato, Masahiko Hatakeyama, Atsushi Iwamura, Tatsuki Fukami, Toshiyuki Kume, Tsuyoshi Yokoi, Miki Nakajima
UDP-Glucuronosyltransferases (UGTs) are major phase II drug-metabolizing enzymes. Each member of the UGT family exhibits a unique but occasionally overlapping substrate specificity and tissue-specific expression pattern. Earlier studies have reported that human UGT1A10 is expressed in the gastrointestinal tract at the mRNA level, but the evaluation at the protein level, especially tissue or cellular localization, has lagged behind because of the lack of a specific antibody. In this study, we prepared a monoclonal antibody against UGT1A10 to elucidate the tissue/cellular distribution and interindividual variability of UGT1A10 protein expression...
July 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28679672/the-impact-of-the-hepatocyte-to-plasma-ph-gradient-on-the-prediction-of-hepatic-clearance-and-drug-drug-interactions-for-cyp2c9-and-cyp3a4-substrates
#12
Luc Raymond Albert Rougee, Michael A Mohutsky, David W Bedwell, Kenneth J Ruterbories, Stephen D Hall
Surrogate assays for drug metabolism and inhibition are traditionally performed in buffer systems at pH 7.4, despite evidence that hepatocyte intracellular pH is 7.0. This pH gradient can result in a pKa-dependent change in intracellular/extracellular concentrations for ionizable drugs that could affect predictions of clearance and P450 inhibition. The effect of microsomal incubation pH on in vitro enzyme kinetic parameters for CYP2C9 (diclofenac, (S)-warfarin) and CYP3A4 (midazolam, dextromethorphan, testosterone) substrates, enzyme specific reversible inhibitors (amiodarone, desethylamiodarone, clozapine, nicardipine, fluconazole, fluvoxamine, itraconazole) and a mechanism-based inhibitor (amiodarone) was investigated...
July 5, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28646080/considerations-from-the-iq-induction-working-group-in-response-to-drug-drug-interaction-guidances-from-regulatory-agencies-focus-on-down-regulation-cyp2c-induction-and-cyp2b6-positive-control
#13
Niresh Hariparsad, Diane Ramsden, Jairam Palamanda, Joshua G Dekeyser, Odette A Fahmi, Jane R Kenny, Heidi Einolf, Michael Mohutsky, Magalie Pardon, Amy Y Siu, Liangfu Chen, Michael Sinz, Barry Jones, Robert Walsky, Shannon Dallas, Suresh K Balani, George Zhang, David Buckley, Donald Tweedie
The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency and the Food and Drug Administration have issued guidances for the conduct of drug-drug interaction (DDI) studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (WG). A team of 20 scientists, from 16 of the 39 pharmaceutical companies, which are members of the IQ Consortium, and three Contract Research Organizations, reviewed the recommendations, focusing initially on the current EMA guidance...
June 23, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28576766/comparative-evaluation-of-plasma-bile-acids-dehydroepiandrosterone-sulfate-hexadecanedioate-and-tetradecanedioate-with-coproporphyrins-i-and-iii-as-markers-of-oatp-inhibition-in-healthy-subjects
#14
Hong Shen, Weiqi Chen, Dieter M Drexler, Sandhya Mandlekar, Vinay K Holenarsipur, Eric E Shields, Robert Langish, Kurex Sidik, Jinping Gan, W Griffith Humphreys, Punit Marathe, Yurong Lai
Multiple endogenous compounds have been proposed as candidate biomarkers to monitor organic anion transporting polypeptide (OATP) function in preclinical species or humans. Recently we have demonstrated that coproporphyrins (CPs) I and III are appropriate clinical markers to evaluate OATP inhibition and recapitulate clinical drug-drug interactions (DDIs). In the present studies, we investigated bile acids (BAs), dehydroepiandrosterone sulfate (DHEAS), hexadecanedioate (HDA), and tetradecanedioate (TDA) in plasma as endogenous probes for OATP inhibition and compared these candidate probes to CPs...
June 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28566285/comparison-of-19f-nmr-and-14c-measurements-for-the-assessment-of-adme-of-byl719-alpelisib-in-humans
#15
Alexander D James, Cyrille Marvalin, Alexandre Luneau, Axel Meissner, Gian Camenisch
The human mass balance study is the definitive study for the assessment of absorption, distribution, metabolism and excretion (ADME) properties of a new chemical entity (NCE) in humans. Traditionally this has been carried out by the administration of radiolabeled drug substances, typically 14C or occasionally 3H, as detection methods for these isotopes allow the absolute quantification of drug related material (DRM) in blood, plasma and excreta. Coupled with the use of analytical techniques such as liquid chromatography-mass spectrometry, a picture of the metabolic fate of a compound can be elucidated...
May 31, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28698302/heme-modification-contributes-to-the-mechanism-based-inactivation-of-human-cytochrome-p450-2j2-by-two-terminal-acetylenic-compounds
#16
Hsia-Lien Lin, Haoming Zhang, Vyvyca J Walker, Jaime D'Agostino, Paul F Hollenberg
The mechanism-based inactivation of human CYP2J2 by three terminal acetylenic compounds: N-(methylsulfonyl)-6-(2-propargyloxyphenyl)hexanamide (MS), 17-octadecynoic acid (OD), and danazol (DZ) was investigated. The loss of hydroxyebastine (OHEB) carboxylation activity in a reconstituted system was time- and concentration-dependent and required NADPH for MS and OD, but not DZ. The kinetic constants for the mechanism-based inactivation of OHEB carboxylation activity were: KI of 6.1 μM and kinact of 0.22 min(-1) for MS and KI of 2...
September 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28663285/inhibitory-effects-of-selected-antituberculosis-drugs-on-common-human-hepatic-cytochrome-p450-and-udp-glucuronosyltransferase-enzymes
#17
Lei Cao, David J Greenblatt, Awewura Kwara
The comorbidities of tuberculosis and diseases such as HIV require long-term treatment with multiple medications. Despite substantial in vitro and in vivo information on effects of rifampicin and isoniazid on human CYPs, there is limited published data regarding the inhibitory effects of other anti-TB drugs on human CYPs and UGTs. The inhibitory effects of five first-line anti-TB drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and rifabutin), and the newly approved bedaquiline, were evaluated for six common human hepatic UGT enzymes (UGT1A1, 1A4, 1A6, 1A9, 2B7 and 2B15) in vitro using HLMs...
September 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28646079/identification-of-flavin-containing-monooxygenase-5-fmo5-as-a-regulator-of-glucose-homeostasis-and-a-potential-sensor-of-gut-bacteria
#18
Flora Scott, Sandra G Gonzalez Malagon, Brett A O'Brien, Diede Fennema, Sunil Veeravalli, Clarissa R Coveney, Ian R Phillips, Elizabeth A Shephard
We have previously identified flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic aging. The aim of the present study was to investigate the role of FMO5 in glucose homeostasis and the impact of diet and gut flora on the phenotype of mice in which the Fmo5 gene has been disrupted (Fmo5(-)(/)(-) mice). In comparison with wild-type (WT) counterparts, Fmo5(-)(/)(-) mice are resistant to age-related changes in glucose homeostasis and maintain the higher glucose tolerance and insulin sensitivity characteristic of young animals...
September 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28646078/stereospecific-metabolism-of-r-and-s-warfarin-by-human-hepatic-cytosolic-reductases
#19
Dustyn A Barnette, Bryce P Johnson, Dakota L Pouncey, Robert Nshimiyimana, Linda P Desrochers, Thomas E Goodwin, Grover P Miller
Coumadin (rac-warfarin) is the most commonly used anticoagulant in the world; however, its clinical use is often challenging because of its narrow therapeutic range and interindividual variations in response. A critical contributor to the uncertainty is variability in warfarin metabolism, which includes mostly oxidative but also reductive pathways. Reduction of each warfarin enantiomer yields two warfarin alcohol isomers, and the corresponding four alcohols retain varying levels of anticoagulant activity. Studies on the kinetics of warfarin reduction have often lacked resolution of parent-drug enantiomers and have suffered from coelution of pairs of alcohol metabolites; thus, those studies have not established the importance of individual stereospecific reductive pathways...
September 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28607029/age-dependent-protein-abundance-of-cytosolic-alcohol-and-aldehyde-dehydrogenases-in-human-liver
#20
Deepak Kumar Bhatt, Andrea Gaedigk, Robin E Pearce, J Steven Leeder, Bhagwat Prasad
Hepatic cytosolic alcohol and aldehyde dehydrogenases (ADHs and ALDHs) catalyze the biotransformation of xenobiotics (e.g., cyclophosphamide and ethanol) and vitamin A. Because age-dependent hepatic abundance of these proteins is unknown, we quantified protein expression of ADHs and ALDH1A1 in a large cohort of pediatric and adult human livers by liquid chromatography coupled with tandem mass spectrometry proteomics. Purified proteins were used as calibrators. Two to three surrogate peptides per protein were quantified in trypsin digests of liver cytosolic samples and calibrator proteins under optimal conditions of reproducibility...
September 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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