The activities of drug inactive ingredients on biological targets.
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
24 07 2020
24 07 2020
Historique:
received:
25
10
2019
accepted:
18
05
2020
entrez:
25
7
2020
pubmed:
25
7
2020
medline:
8
8
2020
Statut:
ppublish
Résumé
Excipients, considered "inactive ingredients," are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant
Identifiants
pubmed: 32703874
pii: 369/6502/403
doi: 10.1126/science.aaz9906
pmc: PMC7960226
mid: NIHMS1674523
doi:
Substances chimiques
Excipients
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
403-413Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM071896
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122481
Pays : United States
Organisme : FDA HHS
ID : U01 FD004979
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Références
Arch Environ Occup Health. 2016 May 3;71(3):170-7
pubmed: 26267674
Xenobiotica. 2012 Apr;42(4):389-97
pubmed: 22054055
J Mol Biol. 1998 Feb 13;276(1):71-84
pubmed: 9514730
J Med Chem. 2013 Nov 27;56(22):8955-71
pubmed: 23919353
J Pharm Pharm Sci. 2015;18(5):844-55
pubmed: 26670370
Nature. 2012 Jun 10;486(7403):361-7
pubmed: 22722194
Mol Pharm. 2014 Sep 2;11(9):3039-47
pubmed: 25115349
Proc Natl Acad Sci U S A. 1990 Mar;87(6):2264-8
pubmed: 2315319
Regul Toxicol Pharmacol. 2007 Apr;47(3):308-16
pubmed: 17218045
Nature. 2018 Mar 29;555(7698):623-628
pubmed: 29555994
Clin Pharmacol Ther. 2017 Mar;101(3):320-323
pubmed: 27557422
Nature. 2009 Nov 12;462(7270):175-81
pubmed: 19881490
Brain Dev. 2013 Mar;35(3):261-4
pubmed: 22658806
Environ Health Perspect. 2015 Jun;123(6):579-89
pubmed: 25690930
Drug Discov Today. 2019 Feb;24(2):417-427
pubmed: 30453059
Nat Biotechnol. 2014 Jun;32(6):583-91
pubmed: 24837663
Int J Mol Sci. 2015 Jan 05;16(1):1008-29
pubmed: 25569083
Proc Natl Acad Sci U S A. 2015 Oct 6;112(40):12498-503
pubmed: 26417083
J Med Chem. 2015 Sep 10;58(17):7076-87
pubmed: 26295373
Nat Biotechnol. 2007 Feb;25(2):197-206
pubmed: 17287757
PLoS One. 2015 Jun 25;10(6):e0131168
pubmed: 26110840
Nat Rev Drug Discov. 2012 Dec;11(12):909-22
pubmed: 23197038
Drugs R D. 2016 Mar;16(1):53-68
pubmed: 26689565
Drugs R D. 2017 Mar;17(1):103-115
pubmed: 27943146
Environ Health Perspect. 2005 Aug;113(8):1015-21
pubmed: 16079072
Pediatrics. 2008 Feb;121(2):e208-14
pubmed: 18245396
Nat Chem Biol. 2008 Nov;4(11):682-90
pubmed: 18936753
Thyroid. 2012 Oct;22(10):1090
pubmed: 22962862
J Med Chem. 2002 Apr 11;45(8):1712-22
pubmed: 11931626
Toxicol Sci. 2011 Apr;120(2):499-506
pubmed: 21252391
Toxicol Appl Pharmacol. 2004 Jul 15;198(2):209-30
pubmed: 15236954
Lancet. 2013 Sep 14;382(9896):951-62
pubmed: 23810019
Eye (Lond). 1989;3 ( Pt 5):581-7
pubmed: 2630335
Elife. 2017 Aug 08;6:
pubmed: 28786378
JAMA. 2003 Oct 1;290(13):1763-6
pubmed: 14519711
Pediatrics. 2004 Sep;114(3):793-804
pubmed: 15342856
Pharmacol Ther. 1999 Nov;84(2):133-56
pubmed: 10596903
Cardiovasc Res. 2003 Apr 1;58(1):32-45
pubmed: 12667944
Nat Biotechnol. 2006 Jul;24(7):805-15
pubmed: 16841068
Nature. 2012 Dec 13;492(7428):215-20
pubmed: 23235874
PLoS One. 2011 Mar 18;6(3):e18035
pubmed: 21437260
J Med Chem. 2014 Apr 24;57(8):3186-204
pubmed: 24151987
Nat Rev Drug Discov. 2006 Dec;5(12):993-6
pubmed: 17139284
J Gerontol A Biol Sci Med Sci. 2015 Aug;70(8):989-95
pubmed: 25733718
Gen Pharmacol. 1997 Oct;29(4):633-8
pubmed: 9352314
Cell Chem Biol. 2017 Jul 20;24(7):858-869.e5
pubmed: 28669525
Drug Saf. 2005;28(2):89-101
pubmed: 15691220
Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11178-83
pubmed: 22711801
J Chem Inf Model. 2008 Apr;48(4):755-65
pubmed: 18335977
J Med Chem. 2007 May 17;50(10):2385-90
pubmed: 17447748
J Mol Biol. 1990 Oct 5;215(3):403-10
pubmed: 2231712
Behav Brain Res. 2011 Sep 30;223(1):107-18
pubmed: 21549155