DOCSLIB.ORG

Acute Aquatic Toxicity of Metofluthrin Metabolites in the Environment

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Acute Aquatic Toxicity of Metofluthrin Metabolites in the Environment J. Pestic. Sci. 38(4), 173–180 (2013) DOI: 10.1584/jpestics.D13-009 Original Article Acute aquatic toxicity of metofluthrin metabolites in the environment Mitsugu Miyamoto,* Akiko Fujiwara, Hitoshi Tanaka and Toshiyuki Katagi Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 4–2–1 Takatsukasa, Takarazuka, Hyogo 665–8555, Japan (Received February 14, 2013; Accepted June 29, 2013) Acute aquatic toxicity of eight major metabolites of the pyrethroid insecticide metofluthrin, potentially formed via oxidation and ester cleavage in the environment, was examined using three representative species, fathead minnow (Pimephales promelas), Daphnia magna and green alga (Pseudokirchneriella subcapitata). All metabolites showed a wide range of toxicity but were more than a hundredfold and tenfold less toxic than metofluthrin to pyrethroid-sensitive (fish and daphnid) and -insensitive (algal) taxa, respectively; 0.44 to >120 mg/L (fish 96-hr LC50), 6.3 to >120 mg/L(daphnid 48-hr EC50), and 2.6 to >110 mg/L (algal 96-hr EyC50). The structural modification via ester cleavage and/or oxidation was found to significantly control the acute aquatic toxicity of the metabolites. The decreased lipophilicity in the metabolites generally resulted in much less acute toxicity, the extent of which was dependent on an introduced functional group such as formyl as a toxicophore and carboxyl causing a higher acid- ity. ​© Pesticide Science Society of Japan Keywords: fathead minnow, Daphnia magna, alga, metofluthrin, ecotoxicity, metabolite. ester linkage, as reported for 4′-OH-bifenthrin.10) Introduction Metofluthrin (I) (SumiOne®, Eminence®) [2,3,5,6- Pyrethroid is one of the most important chemical classes of in- tetrafluoro-4-(methoxymethyl) benzyl(1R,3R)-2,2-dimethyl-3- secticide for both agricultural and public hygiene uses; it is not ((1EZ)-prop-1-enyl)cyclopropanecarboxylate] is a new pyre- only exhibits an excellent biological activity but also readily de- throid insecticide with an extremely high knockdown activ- grades biotically and abiotically in the environment.1–4) It can ity, especially against mosquitoes.11,12) Similarly to other pyre- be well understood from its mode of action that pyrethroid is throids, I exhibits high acute toxicity to common carp (Cyprinus highly toxic to fish and arthropods (crustaceans and insects) in carpio) and rainbow trout (Oncorhynchus mykiss) with 96-hr general, but extremely less toxic to other invertebrates such as LC50 of 0.0012 and 0.00306 mg/L, respectively, and to Daphnia 5) mollusk and aquatic plants including algae. Rapid degradation magna with 48-hr EC50 of 0.0047 mg/L, while it is much less of pyrethroid in the environment makes its aquatic risks under toxic to green algae (Pseudokirchneriella subcapitata) with 72-hr 12–14) practical uses acceptable and manageable, while ecological risk EbC50 of 0.16 mg/L. Considering the typical use pattern of I, assessment of corresponding metabolites is very limited at the which is distributed into the air by vaporization as a mosquito present. In general, metabolic transformation of a pesticide ei- adulticide, its direct emission into the aquatic environment is ther destroys a toxicophore structure or introduces a new func- most unlikely. Even if emitted into the aquatic environment, I tional group, generally leading to increased molecular hydro- degrades via either hydrolysis to the corresponding acid and al- philicity, and the changes in the mode of action or the uptake cohol moieties or sunlight photolysis with successive oxidation potential result in less toxicity of metabolites than the parent.6) at the prop-1-enyl side chain with no remarkable change in an Most metabolites formed via ester cleavage show far less toxicity E/Z isomer ratio because of similar degradation rates and no 15) (LC50, EC50) to sensitive taxa by 2–6 orders of magnitude than isomerization. Furthermore, when I is distributed in the ter- do corresponding pyrethroids,7–9) while limited information is restrial environment, aerobic microbes in soil rapidly metabolize available on the aquatic toxicity of metabolites having an intact it via ester cleavage followed by successive oxidation16) or it is photodegraded by sunlight on the soil surface.17) Eight major * To whom correspondence should be addressed. metabolites (II–IX) detected through environmental fate stud- E-mail: [email protected] ies, as shown in Fig. 1, have unique chemical structures different Published online September 9, 2013 from other pyrethroids. © Pesticide Science Society of Japan The objective of this study has been to determine basic 174 M. Miyamoto et al. Journal of Pesticide Science Fig. 1. Structures of metofluthrin metabolites in the environment with their route of formation. aquatic ecotoxicological profiles of the major metabolites identi- on a standard commercial fish food (TetraMin®, Tetra Werke, fied in environmental fate studies of metofluthrin, using three Germany), and juveniles (total length, 1.5–2.9 cm) were used standard aquatic species (fish, daphnid, algal), in relation to the for bioassays. D. magna cultures, held at ca. 20°C with a 16-hr structural modification from metofluthrin. daylight photoperiod, regularly fed on commercially available chlorella (Chlorella V12, Chlorella Industry Co., Ltd., Tokyo, Materials and Methods Japan), and <24-hr-old neonates were used. Elendt M4 medium 1. Chemicals referenced in OECD guideline 20218) or ASTM Hard Reconsti- The metabolites of I (II–VI and VIII) were prepared as test tuted Fresh Water19) was used as culture water. Pure water with substances in our laboratory according to the reported meth- an electrical resistivity of more than 17 MΩ cm, provided by a ods.11,15–17) The chemical purity of each metabolite was deter- Barnstead E-pure D4643 (4Module E-pure, Barnstead Ther- mined by HPLC to be greater than 98%. VII (99.4%) and IX molyne Co., Iowa, USA), was used to prepare the culture media. (>97%) were purchased from Showa Denko K.K. (Tokyo, Japan) Fathead minnows and D. magna were not fed during the bioas- and Tokyo Kasei Kogyo Co., Ltd. (Tokyo, Japan), respectively, says. Precultures of P. subcapitata were prepared prior to each and used without further purification. All other chemicals were bioassay from stocks in a refrigerator and incubated at 23–26°C of a reagent grade and purchased from commercial suppliers in the medium referenced in OECD guideline 20118) under con- unless otherwise noted. tinuous shaking (Multishaker MMS-310, Tokyo Rikakikai Co., Ltd.) and illumination (fluorescent bulbs). 2. Test organisms Fathead minnow (P. promelas), D. magna, and the unicellular 3. Bioassays green algal species, P. subcapitata (ATCC22662), were chosen The acute toxicity of each metabolite on three species was ex- as test species because of recommendations in international test amined basically in accordance with the corresponding inter- guidelines, such as those of the OECD (Organisation for Eco- national guidelines of the OECD.18) The same types of media for nomic Co-operation and Development).18) Parental organisms culturing were used for the bioassays. The aqueous solution of a were originally obtained from the National Institute for Envi- metabolite (V–IX) was prepared at a desired concentration by ronmental Studies (Ibaraki, Japan) for fathead minnows and its direct dissolution, followed by serial dilution with the media. from Sumika Technoservice Corporation (Hyogo, Japan) for Otherwise, a metabolite (II–IV) was first dissolved inN ,N- D. magna and P. subcapitata. The cultures of fathead minnows dimethylformamide (DMF), followed by dilution with the media were held in tap water dechlorinated with activated charcoal at at 0.1 mL DMF/L. When a test substance was partly dissolved ca. 25°C with a 16-hr daylight photoperiod. They regularly fed in the media, the supernatant by decantation was used for the Vol. 38, No. 4, 173–180 (2013) Acute aquatic toxicity of metofluthrin metabolites in the environment 175 exposure and chemical analysis. The chemical analysis of each and the limited buffering capacity of the OECD medium, the metabolite was regularly conducted in each test, together with pH effect on algal toxicity was conveniently examined for VI at measurements of temperature (Multi-thermometer, JAPAN PET 100 mg/L by readjusting the pH of the exposure OECD medium DRUGS Co., Ltd.) and pH (Model B-212, Horiba Ltd., Japan). to ca. 8 with 0.1 N NaOH. Except in the algal tests, the dissolved oxygen (DO) concentra- tion in the test solution was also measured (SevenGo pro, Met- 4. Chemical analysis tler Toledo, Columbus, Ohio, USA). At least at the initiation and termination of exposure, the con- 3.1. Fish acute toxicity test centration of each metabolite was determined by direct HPLC Groups of seven fathead minnows were exposed without rep- analysis of each test solution after an appropriate dilution. A Shi- lication in 1000 mL of each test solution for 96 hr under static madzu HPLC system (LC-10AD pump, SCL-10A system con- conditions using 1-L glass beakers. In the case of III, 20-L size troller and SPD-10A UV detector at 230 nm) equipped with an stainless steel vessels (27×27×32 cm) filled with a 10-L test L-column ODS (5 µm, 4.6mmϕ×150 mm; Chemicals Evaluation solution were used instead under static-renewal (every 48 hr) and Research Institute, Japan, Tokyo) was operated at a flow rate conditions to maintain exposure concentrations. The test vessels of 1.0 mL/min under the isocratic condition. The mixing ratio were partly immersed in a temperature-controlled water bath (v/v) of acetonitrile/0.05% trifluoroacetic acid water as a mobile maintained at 25± 1°C under a photoperiod of 16 hr/day using phase and the typical retention time of each metabolite in paren- fluorescent bulbs (ca. 500–1000 lx). Except in the cases of III thesis are as follows: II, 35/65 (13.3, 16.2, 17.3, and 18.5 min); and VI, the test solutions were mildly aerated to maintain the III, 3/2 (6.8 min); IV, 2/3 (17.5 min); V, 2/3 (8.1 min); VI, 1/9 DO levels.
Load more

Recommended publications
  • Using Toxicity Tests in Ecological Risk Assessment Toxicity Tests Are Used to Expose Test Organisms to a 2
    United States Office of Publication 9345.0-05I Environmental Solid Waste and March 1994 Protection Emergency Response Agency ECO Update Office of Emergency Remedial Response Intermittent Bulletin Hazardous Site Evaluation Division (5204G) Volume 2 Number1 Using Toxicity Tests in Ecological Risk Assessment Toxicity tests are used to expose test organisms to a 2. Toxicity tests can evaluate the aggregate toxic effects of medium—water, sediment, or soil—and evaluate the effects of all contaminants in a medium. Many Superfund sites present contamination on the survival, growth, reproduction, behavior a complex array of contaminants, with a mixture of potentially and/or other attributes of these organisms. These tests may harmful substances present in the media. At such sites, help to determine whether the contaminant concentrations in a chemical data alone cannot accurately predict the toxicity of site’s media are high enough to cause adverse effects in the contaminants. Rather, toxicity tests measure the aggregate organisms. Generally, toxicity tests involve collecting effects of contaminated media on organisms. These effects samples of media from a site and sending them to a toxicity result from characteristics of the medium itself (such as laboratory, where the tests are performed. On occasion hardness and pH, in the case of water), interactions among investigators1 measure toxicity by exposing test organisms to contaminants, and interactions between contaminants and soil or water on site—these are known as in situ tests. media. Consequently, observed toxicity test results may often vary from those predicted by chemical data alone. As the general guidelines at the end of this Bulletin indicate, not all sites require toxicity tests.
    [Show full text]
  • Gene-Signature-Derived Ic50s/Ec50s Reflect the Potency of Causative
    www.nature.com/scientificreports OPEN Gene-signature-derived IC50s/EC50s refect the potency of causative upstream targets and downstream phenotypes Stefen Renner1 ✉ , Christian Bergsdorf1, Rochdi Bouhelal1, Magdalena Koziczak-Holbro2, Andrea Marco Amati1,6, Valerie Techer-Etienne1, Ludivine Flotte2, Nicole Reymann1, Karen Kapur3, Sebastian Hoersch3, Edward James Oakeley4, Ansgar Schufenhauer1, Hanspeter Gubler3, Eugen Lounkine5,7 & Pierre Farmer1 ✉ Multiplexed gene-signature-based phenotypic assays are increasingly used for the identifcation and profling of small molecule-tool compounds and drugs. Here we introduce a method (provided as R-package) for the quantifcation of the dose-response potency of a gene-signature as EC50 and IC50 values. Two signaling pathways were used as models to validate our methods: beta-adrenergic agonistic activity on cAMP generation (dedicated dataset generated for this study) and EGFR inhibitory efect on cancer cell viability. In both cases, potencies derived from multi-gene expression data were highly correlated with orthogonal potencies derived from cAMP and cell growth readouts, and superior to potencies derived from single individual genes. Based on our results we propose gene-signature potencies as a novel valid alternative for the quantitative prioritization, optimization and development of novel drugs. Gene expression signatures are widely used in the feld of translational medicine to defne disease sub-types1, severity2 and predict treatment outcome3. Bridging this technology to early drug discovery was previously pro- posed years ago4,5 but its prohibitive costs limited this approach. Te recent advancement of massively parallel gene expression technologies such as RASL-seq.6, DRUG-seq.7, QIAseq.8,9, PLATE-seq.10, or LINCS L100011 are now transforming the feld of compound profling, enabling larger scale profling and screening experiments at a more afordable cost12–17.
    [Show full text]
  • Clinical Pharmacokinetics 38
    Clin Pharmacokinet 2000 Jun; 38 (6): 505-518 ORIGINAL RESEARCH ARTICLE 0312-5963/00/0006-0505/$20.00/0 © Adis International Limited. All rights reserved. Pharmacokinetic-Pharmacodynamic Modelling of the Antipyretic Effect of Two Oral Formulations of Ibuprofen Iñaki F. Trocóniz,1 Santos Armenteros,2 María V. Planelles,3 Julio Benítez,4 Rosario Calvo5 and Rosa Domínguez2 1 Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona, Spain 2 Medical Department, Laboratorios Knoll S.A., Madrid, Spain 3 Department of Paediatrics, Clinic Hospital, Valencia, Spain 4 Department of Pharmacology, Faculty of Medicine, University of Extremadura, Badajoz, Spain 5 Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Lejona, Spain Abstract Objective: To analyse the population pharmacokinetic-pharmacodynamic relation- ships of racemic ibuprofen administered in suspension or as effervescent granules with the aim of exploring the effect of formulation on the relevant pharmaco- dynamic parameters. Design: The pharmacokinetic model was developed from a randomised, cross- over bioequivalence study of the 2 formulations in healthy adults. The pharmaco- dynamic model was developed from a randomised, multicentre, single dose efficacy and safety study of the 2 formulations in febrile children. Patients and participants: Pharmacokinetics were studied in 18 healthy volun- teers aged 18 to 45 years, and pharmacodynamics were studied in 103 febrile children aged between 4 and 16 years with bodyweight ≥25kg. Methods: The pharmacokinetic study consisted of two 1-day study occasions, each separated by a 1-week washout period. On each occasion ibuprofen 400mg was administered orally as suspension or granules. The time course of the anti- pyretic effect was evaluated in febrile children receiving a single oral dose of 7 mg/kg in suspension or 200 or 400mg as effervescent granules.
    [Show full text]
  • Synthèse Et Evaluation De Nouveau Agents De Protection Contre Les Rayonnements Ionisants Brice Nadal
    Synthèse et Evaluation de nouveau agents de protection contre les rayonnements ionisants Brice Nadal To cite this version: Brice Nadal. Synthèse et Evaluation de nouveau agents de protection contre les rayonnements ion- isants. Chimie. Université Paris Sud - Paris XI, 2009. Français. tel-00447089 HAL Id: tel-00447089 https://tel.archives-ouvertes.fr/tel-00447089 Submitted on 14 Jan 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. N° D’ORDRE : 9602 UNIVERSITÉ PARIS SUD XI FACULTÉ DES SCIENCES D’ORSAY THÈSE DE DOCTORAT Présentée en vue de l’obtention du grade de DOCTEUR EN SCIENCES DE L’UNIVERSITÉ PARIS SUD XI Spécialité Chimie Organique Par Brice NADAL Ingénieur CPE Lyon Synthèse et évaluation de nouveaux agents de protection contre les rayonnements ionisants Soutenue le 29 octobre 2009 devant la commission d’examen : Professeur Cyrille Kouklovsky Président Docteur Paul-Henri Ducrot Rapporteur Professeur Olivier Piva Rapporteur Docteur Claude Lion Examinateur Docteur Pierre Bischoff Examinateur Docteur Thierry Le Gall Directeur de thèse N° D’ORDRE
    [Show full text]
  • Introduction
    Guidance for Assay Development & HTS March 2007 Version 5 Section I: Introduction Introduction Copyright © 2005, Eli Lilly and Company and the National Institutes of Health Chemical Genomics Center. All Rights Reserved. For more information, please review the Privacy Policy and Site Usage and Agreement. Table of Contents A. INTRODUCTION This document is written to provide guidance to investigators that are interested in developing assays useful for the evaluation of compound collections to identify chemical probes that modulate the activity of biological targets. Originally written as a guide for therapeutic projects teams within a major pharmaceutical company, this manual has been adapted to provide guidelines for: a. Identifying potential assay formats compatible with High Throughput Screen (HTS), and Structure Activity Relationship (SAR) b. Developing optimal assay reagents c. Optimizing assay protocol with respect to sensitivity, dynamic range, signal intensity and stability d. Adopting screening assays to automation and scale up in microtiter plate formats e. Statistical validation of the assay performance parameters f. Secondary follow up assays for chemical probe validation and SAR refinement g. Data standards to be followed in reporting screening and SAR assay results. General definition of biological assays This manual is intended to provide guidance in the area of biological assay development, screening and compound evaluation. In this regard an assay is defined by a set of reagents that produce a detectable signal allowing a biological process to be quantified. In general, the quality of an assay is defined by the robustness and reproducibility of this signal in the absence of any test compounds or in the presence of inactive compounds.
    [Show full text]
  • An Online Tool for Calculating and Mining Dose–Response Data Nicholas A
    Clark et al. BMC Cancer (2017) 17:698 DOI 10.1186/s12885-017-3689-3 SOFTWARE Open Access GRcalculator: an online tool for calculating and mining dose–response data Nicholas A. Clark1†, Marc Hafner2†, Michal Kouril3, Elizabeth H. Williams2, Jeremy L. Muhlich2, Marcin Pilarczyk1, Mario Niepel2, Peter K. Sorger2 and Mario Medvedovic1* Abstract Background: Quantifying the response of cell lines to drugs or other perturbagens is the cornerstone of pre-clinical drug development and pharmacogenomics as well as a means to study factors that contribute to sensitivity and resistance. In dividing cells, traditional metrics derived from dose–response curves such as IC50, AUC, and Emax, are confounded by the number of cell divisions taking place during the assay, which varies widely for biological and experimental reasons. Hafner et al. (Nat Meth 13:521–627, 2016) recently proposed an alternative way to quantify drug response, normalized growth rate (GR) inhibition, that is robust to such confounders. Adoption of the GR method is expected to improve the reproducibility of dose–response assays and the reliability of pharmacogenomic associations (Hafner et al. 500–502, 2017). Results: We describe here an interactive website (www.grcalculator.org) for calculation, analysis, and visualization of dose–response data using the GR approach and for comparison of GR and traditional metrics. Data can be user-supplied or derived from published datasets. The web tools are implemented in the form of three integrated Shiny applications (grcalculator, grbrowser, and grtutorial) deployed through a Shiny server. Intuitive graphical user interfaces (GUIs) allow for interactive analysis and visualization of data. The Shiny applications make use of two R packages (shinyLi and GRmetrics) specifically developed for this purpose.
    [Show full text]
  • Oecd Guideline for the Testing of Chemicals
    XXX OECD GUIDELINE FOR THE TESTING OF CHEMICALS Stably Transfected Human Androgen Receptor-α Transcriptional Activation Assay for Detection of Androgenic Agonist Agonist/Antagonist Activity of Chemicals (Version 2010 Nov.25) INTRODUCTION 1. The OECD initiated a high-priority activity in 1998 to revise existing, and to develop new, Test Guidelines for the screening and testing of potential endocrine disrupting chemicals. The OECD conceptual framework for testing and assessment of potential endocrine disrupting chemicals comprises five levels, each level corresponding to a different level of biological complexity (1). The Transcriptional Activation (TA) assay described in this Test Guideline is a level 2 “in vitro assay, providing mechanistic information”. The validation study of the Stably Transfected Transactivation Assay (STTA) by Chemicals Evaluation and Research Institute (CERI) in Japan using the AR-EcoScreenTM cell line to detect Androgenic agonist/antagonist activities mediated through human androgen receptor demonstrated the relevance and reliability of the assay for its intended purpose (2). 2. In vitro TA assays are based upon the production of a reporter gene product induced by a chemical, following binding of the chemical to a specific receptor and subsequent downstream transcriptional activation. TA assays using activation of reporter genes are screening assays that have long been used to evaluate the specific gene expression regulated by specific nuclear receptors, such as the estrogen receptors (ERs) and androgen receptor (AR) (3)(4)(5)(6). They have been proposed for the detection of nuclear receptor mediated transactivation (1)(3)(4). Several in vitro TA and receptor binding assays are currently at validation at national, European and international levels, but are not yet close to completion and full assessment of their validation status.
    [Show full text]
  • Analyzing Binding Data UNIT 7.5 Harvey J
    Analyzing Binding Data UNIT 7.5 Harvey J. Motulsky1 and Richard R. Neubig2 1GraphPad Software, La Jolla, California 2University of Michigan, Ann Arbor, Michigan ABSTRACT Measuring the rate and extent of radioligand binding provides information on the number of binding sites, and their afÞnity and accessibility of these binding sites for various drugs. This unit explains how to design and analyze such experiments. Curr. Protoc. Neurosci. 52:7.5.1-7.5.65. C 2010 by John Wiley & Sons, Inc. Keywords: binding r radioligand r radioligand binding r Scatchard plot r r r r r r receptor binding competitive binding curve IC50 Kd Bmax nonlinear regression r curve Þtting r ßuorescence INTRODUCTION A radioligand is a radioactively labeled drug that can associate with a receptor, trans- porter, enzyme, or any protein of interest. The term ligand derives from the Latin word ligo, which means to bind or tie. Measuring the rate and extent of binding provides information on the number, afÞnity, and accessibility of these binding sites for various drugs. While physiological or biochemical measurements of tissue responses to drugs can prove the existence of receptors, only ligand binding studies (or possibly quantitative immunochemical studies) can determine the actual receptor concentration. Radioligand binding experiments are easy to perform, and provide useful data in many Þelds. For example, radioligand binding studies are used to: 1. Study receptor regulation, for example during development, in diseases, or in response to a drug treatment. 2. Discover new drugs by screening for compounds that compete with high afÞnity for radioligand binding to a particular receptor.
    [Show full text]
  • Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer S
    Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2020/06/24/dmd.119.090092.DC1 1521-009X/48/9/796–803$35.00 https://doi.org/10.1124/dmd.119.090092 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 48:796–803, September 2020 Copyright ª 2020 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer s P. Kellie Turner, Stephen D. Hall, Sonya C. Chapman, Jessica L. Rehmel, Jane E. Royalty, Yingying Guo, and Palaniappan Kulanthaivel Eli Lilly and Company, Indianapolis, Indiana (P.K.T., S.D.H., S.C.C., J.L.R., Y.G., P.K.) and Covance Early Clinical Development, Madison, Wisconsin (J.E.R.) Received January 10, 2020; accepted May 19, 2020 ABSTRACT Downloaded from Abemaciclib is an orally administered, potent inhibitor of cyclin- changes were observed for midazolam [area under the concen- dependent kinases 4 and 6 and is metabolized extensively by tration versus time curve from zero to infinity (AUC0–inf) (13% lower), CYP3A4. The effects of abemaciclib on several CYPs were qualified Cmax (15% lower)], caffeine [AUC0–inf (56% higher)], and para- in vitro and subsequently evaluated in a clinical study. In vitro, human xanthine: caffeine [area under the concentration versus time hepatocytes were treated with vehicle, abemaciclib, or abemaciclib curve from 0 to 24 hours ratio (was approximately 30% lower)]. metabolites [N-desethylabemaciclib (M2) or hydroxyabemaciclib However, given the magnitude of the effect, these changes are dmd.aspetjournals.org (M20)].
    [Show full text]
  • Dose–Response Analysis When There Is a Correlation Between Affinity and Efficacy
    1521-0111/89/2/297–302$25.00 http://dx.doi.org/10.1124/mol.115.102509 MOLECULAR PHARMACOLOGY Mol Pharmacol 89:297–302, February 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Dose–Response Analysis When There Is a Correlation between Affinity and Efficacy Anthony Auerbach Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York Received November 13, 2015; accepted December 10, 2015 ABSTRACT Downloaded from The shape of a concentration–response curve (CRC) is de- acetylcholine receptors there is an exponential relationship termined by underlying equilibrium constants for agonist between these two equilibrium dissociation constants. Conse- binding and receptor conformational change. Typically, ago- quently, knowledge of two receptor-specific, agonist-independent nists are characterized by the empirical CRC parameters constants—the activation equilibrium constant without agonists efficacy (the maximum response), EC50 (the concentration that (E0) and the affinity-correlation exponent (M)—allows an entire produces a half-maximum response), and the Hill coefficient CRC to be calculated from a measurement of either efficacy or (the maximum slope of the response). Ligands activate recep- affinity. I describe methods for estimating the CRCs of partial molpharm.aspetjournals.org tors because they bind with higher affinity to the active versus agonists in receptors that have a correlation between affinity resting conformation, and in skeletal muscle nicotinic and efficacy. 21 21 for binding (10,000 s /[L]×100 (mMs) ;Kd 5 100 mM) and forward/ Introduction 21 21 backward rate constants for activation (1000 s /2000 s ;E2 5 0.5).
    [Show full text]
  • Applicability of Drug Response Metrics for Cancer Studies Using Biomaterials Elizabeth A
    bioRxiv preprint doi: https://doi.org/10.1101/408583; this version posted September 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Applicability of Drug Response Metrics for Cancer Studies using Biomaterials Elizabeth A. Brooks1$, Sualyneth Galarza1$, Maria F. Gencoglu1$, R. Chase Cornelison2, Jennifer M. Munson2*, and Shelly R. Peyton1* 1Department of Chemical Engineering, University of Massachusetts Amherst, 240 Thatcher RoaD, Amherst, MA 01003-9364, United States 2Department of BiomeDical Engineering anD Mechanics, Virginia Tech University, 325 Stanger Street, Blacksburg VA 24061, UniteD States $These authors contributeD equally *co-corresponDing authors Abstract: Bioengineers have built increasingly sophisticated models of the tumor microenvironment in which to study cell-cell interactions, mechanisms of cancer growth and metastasis, and to test new potential therapies. These models allow researchers to culture cells in conditions that include features of the in vivo tumor microenvironment (TME) implicated in regulating cancer progression, such as ECM stiffness, integrin binding to the ECM, immune and stromal cells, growth factor and cytokine depots, and a 3D geometry more representative of the TME than tissue culture polystyrene (TCPS). These biomaterials could be particularly useful for drug screening applications to make better predictions of efficacy, offering better translation to preclinical in vivo models and clinical trials. However, it can be challenging to compare drug response reports across different platforms and conditions in the current literature. This is, in part, as a result of inconsistent reporting and use of drug response metrics, and vast differences in cell growth rates across a large variety of biomaterial design.
    [Show full text]
  • An in Vitro Method for Benchmarking of CRISPR-Associated Endonucleases
    An in vitro method for benchmarking of CRISPR-associated endonucleases Eric Tillotson1, Gregory Gotta1, Katherine Loveluck1, John Zuris1, Barrett Steinberg1, Tongyao Wang1, Ramya Viswanathan1, Elise Keston-Smith1, Joost Mostert1, Luis Barrera1, Christopher Wilson1, Vic Myer1, Hari Jayaram1 1Editas Medicine, 11 Hurley Street, Cambridge, MA. 02141 Introduction In vitro Benchmarking of CRISPR-associated Nucleases Direct delivery of Cas9 or Cpf1 ribonucleoprotein (RNP) complexes to a cells by electroporation is emerging as an important delivery mode for ex D N M T 1 _ 0 1 D N M T 1 _ 2 6 D N M T 1 _ 1 6 2 P D 1 _ 0 2 P D 1 _ 0 8 1 .0 1 .0 1 .0 1 .0 1 .0 vivo gene editing therapies. Understanding the dose/efficacy relationship S p S p S p S p S p d S a u d S a u d S a u d S a u d S a u e e e of the delivered RNP is a key step in optimizing a therapeutic. An e e v v v v v a a H iF i a H iF i H iF i a H iF i a H iF i e e e l l e e l essential requirement in accurately establishing this relationship and l l C 0 .5 C 0 .5 C 0 .5 C 0 .5 e c a s e c a s C 0 .5 e c a s e c a s e c a s n n n n n o o o i i o o i determining RNP quality is measuring the in vitro activity of a given RNP i i t a s w t t A s R R t A s R V R t a s w t t A s R R c c c c c a a a a a r r r r L b L b r complex in a standardized manner.
    [Show full text]