In vitro evaluation suggests fenfluramine and norfenfluramine are unlikely to act as perpetrators of drug interactions.
Dravet syndrome
drug transporter
drug-drug interactions
fenfluramine
perpetrator potential
Journal
Pharmacology research & perspectives
ISSN: 2052-1707
Titre abrégé: Pharmacol Res Perspect
Pays: United States
ID NLM: 101626369
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
15
03
2022
accepted:
06
04
2022
entrez:
23
5
2022
pubmed:
24
5
2022
medline:
25
5
2022
Statut:
ppublish
Résumé
Studies support the safety and efficacy of fenfluramine (FFA) as an antiseizure medication (ASM) in Dravet syndrome, Lennox-Gastaut syndrome, or CDKL5 deficiency disorder, all pharmacoresistant developmental and epileptic encephalopathies. However, drug-drug interactions with FFA in multi-ASM regimens have not been fully investigated. We characterized the perpetrator potential of FFA and its active metabolite, norfenfluramine (nFFA), in vitro by assessing cytochrome P450 (CYP450) inhibition in human liver microsomes, CYP450 induction in cultured human hepatocytes, and drug transporter inhibition potential in permeability or cellular uptake assays. Mean plasma unbound fraction was ~50% for both FFA and nFFA, with no apparent concentration dependence. FFA and nFFA were direct in vitro inhibitors of CYP2D6 (IC
Identifiants
pubmed: 35599347
doi: 10.1002/prp2.959
pmc: PMC9124818
doi:
Substances chimiques
Membrane Transport Proteins
0
Norfenfluramine
1886-26-6
Fenfluramine
2DS058H2CF
Cytochrome P-450 Enzyme System
9035-51-2
Cytochrome P-450 CYP1A2
EC 1.14.14.1
Cytochrome P-450 CYP2B6
EC 1.14.14.1
Cytochrome P-450 CYP3A
EC 1.14.14.1
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e00959Informations de copyright
© 2022 Zogenix, Inc. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
Références
Am J Health Syst Pharm. 1997 Sep 15;54(18):2059-72
pubmed: 9377205
Epilepsia. 2021 Jul;62(7):e98-e102
pubmed: 33979451
J Pharm Pharmacol. 1967 Dec;19:Suppl:42S-49S
pubmed: 4383855
Nucleic Acids Res. 2018 Jan 4;46(D1):D1091-D1106
pubmed: 29149325
Xenobiotica. 1992 Nov;22(11):1251-66
pubmed: 1492418
Drug Metab Dispos. 2009 Oct;37(10):2045-54
pubmed: 19608694
Pediatr Neurol. 2017 Mar;68:18-34.e3
pubmed: 28284397
Lancet. 2020 Dec 21;394(10216):2243-2254
pubmed: 31862249
Drug Metab Dispos. 2016 Mar;44(3):453-9
pubmed: 26668209
Clin Pharmacol Ther. 2013 Jul;94(1):52-63
pubmed: 23588305
CNS Drugs. 2013 Mar;27(3):175-84
pubmed: 23397290
J Clin Psychopharmacol. 1998 Aug;18(4):338-41
pubmed: 9690701
Epilepsia. 2017 Jul;58(7):1234-1243
pubmed: 28542801
Epileptic Disord. 2014 Dec;16(4):409-31
pubmed: 25515681
Clin Pharmacol Ther. 2014 Feb;95(2):189-98
pubmed: 24048277
Epilepsy Behav. 2018 Sep;86:131-137
pubmed: 30006259
Xenobiotica. 2009 Jun;39(6):430-43
pubmed: 19480549
Drug Metab Dispos. 2008 Aug;36(8):1698-708
pubmed: 18490437
Int J Clin Pharmacol Ther. 2019 Jan;57(1):11-19
pubmed: 30336805
Drug Metab Dispos. 2015 Jan;43(1):163-81
pubmed: 25297949
Nat Rev Drug Discov. 2010 Mar;9(3):215-36
pubmed: 20190787
Pharmacol Res Perspect. 2022 Jun;10(3):e00958
pubmed: 35599345
Pharmacol Res Perspect. 2022 Jun;10(3):e00959
pubmed: 35599347
J Pharmacol Exp Ther. 2016 Dec;359(3):401-410
pubmed: 27758931
Drug Metab Dispos. 2008 Sep;36(9):1971-4
pubmed: 18519654
Drug Metab Dispos. 2015 Nov;43(11):1744-50
pubmed: 26354951
Drug Metab Dispos. 2006 Apr;34(4):608-11
pubmed: 16415114
Toxicol Sci. 2006 Dec;94(2):261-71
pubmed: 16945988
Expert Opin Drug Metab Toxicol. 2010 Nov;6(11):1399-416
pubmed: 20955108
N Engl J Med. 2018 May 17;378(20):1888-1897
pubmed: 29768152
Arch Biochem Biophys. 1996 Jul 15;331(2):145-69
pubmed: 8660694
JAMA Neurol. 2020 Mar 1;77(3):300-308
pubmed: 31790543
Pharm Res. 2006 Jun;23(6):1089-116
pubmed: 16718615
Clin Pharmacol Drug Dev. 2019 Nov;8(8):1009-1031
pubmed: 30791225
Pharmacogenet Genomics. 2013 Apr;23(4):236-41
pubmed: 23407051
Paediatr Drugs. 2016 Jun;18(3):197-208
pubmed: 26966048
Br J Pharmacol. 2021 Oct;178 Suppl 1:S27-S156
pubmed: 34529832
Drug Metab Rev. 2014 Feb;46(1):86-95
pubmed: 24160757
Drug Metab Dispos. 2013 Oct;41(10):1859-66
pubmed: 23920221
Expert Opin Drug Discov. 2017 Nov;12(11):1105-1115
pubmed: 28820269
Br J Pharmacol. 2021 Oct;178 Suppl 1:S412-S513
pubmed: 34529826
Br J Pharmacol. 2021 Oct;178 Suppl 1:S313-S411
pubmed: 34529828
Expert Rev Neurother. 2010 Jan;10(1):119-40
pubmed: 20021326
Toxicol Appl Pharmacol. 2004 Sep 15;199(3):193-209
pubmed: 15364537
Pharmacol Rep. 2017 Jun;69(3):504-511
pubmed: 28343093
Epilepsy Behav. 2015 Mar;44:104-9
pubmed: 25666511
Cureus. 2018 Aug 13;10(8):e3134
pubmed: 30410820
Clin Pharmacokinet. 1986 Nov-Dec;11(6):483-504
pubmed: 3542339