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In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters
APINACA (known as AKB48, N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide), an indazole carboxamide synthetic cannabinoid, has been used worldwide as a new psychoactive substance. Drug abusers take various drugs concomitantly, and therefore, it is necessary to characterize the potential of APINACA...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720883/ https://www.ncbi.nlm.nih.gov/pubmed/31430908 http://dx.doi.org/10.3390/molecules24163000 |
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author | Kim, Sunjoo Choi, Won-Gu Kwon, Mihwa Lee, Sowon Cho, Yong-Yeon Lee, Joo Young Kang, Han Chang Song, Im-Sook Lee, Hye Suk |
author_facet | Kim, Sunjoo Choi, Won-Gu Kwon, Mihwa Lee, Sowon Cho, Yong-Yeon Lee, Joo Young Kang, Han Chang Song, Im-Sook Lee, Hye Suk |
author_sort | Kim, Sunjoo |
collection | PubMed |
description | APINACA (known as AKB48, N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide), an indazole carboxamide synthetic cannabinoid, has been used worldwide as a new psychoactive substance. Drug abusers take various drugs concomitantly, and therefore, it is necessary to characterize the potential of APINACA-induced drug–drug interactions due to the modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of APINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) in human liver microsomes, as well as on the transport activities of six solute carrier transporters and two efflux transporters in transporter-overexpressed cells, were investigated. APINACA exhibited time-dependent inhibition of CYP3A4-mediated midazolam 1′-hydroxylation (K(i), 4.5 µM; k(inact), 0.04686 min(−1)) and noncompetitive inhibition of UGT1A9-mediated mycophenolic acid glucuronidation (K(i), 5.9 µM). APINACA did not significantly inhibit the CYPs 1A2, 2A6, 2B6, 2C8/9/19, or 2D6 or the UGTs 1A1, 1A3, 1A4, 1A6, or 2B7 at concentrations up to 100 µM. APINACA did not significantly inhibit the transport activities of organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, P-glycoprotein, or breast cancer resistance protein at concentrations up to 250 μM. These data suggest that APINACA can cause drug interactions in the clinic via the inhibition of CYP3A4 or UGT1A9 activities. |
format | Online Article Text |
id | pubmed-6720883 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-67208832019-09-10 In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters Kim, Sunjoo Choi, Won-Gu Kwon, Mihwa Lee, Sowon Cho, Yong-Yeon Lee, Joo Young Kang, Han Chang Song, Im-Sook Lee, Hye Suk Molecules Article APINACA (known as AKB48, N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide), an indazole carboxamide synthetic cannabinoid, has been used worldwide as a new psychoactive substance. Drug abusers take various drugs concomitantly, and therefore, it is necessary to characterize the potential of APINACA-induced drug–drug interactions due to the modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of APINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) in human liver microsomes, as well as on the transport activities of six solute carrier transporters and two efflux transporters in transporter-overexpressed cells, were investigated. APINACA exhibited time-dependent inhibition of CYP3A4-mediated midazolam 1′-hydroxylation (K(i), 4.5 µM; k(inact), 0.04686 min(−1)) and noncompetitive inhibition of UGT1A9-mediated mycophenolic acid glucuronidation (K(i), 5.9 µM). APINACA did not significantly inhibit the CYPs 1A2, 2A6, 2B6, 2C8/9/19, or 2D6 or the UGTs 1A1, 1A3, 1A4, 1A6, or 2B7 at concentrations up to 100 µM. APINACA did not significantly inhibit the transport activities of organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)1, OCT2, P-glycoprotein, or breast cancer resistance protein at concentrations up to 250 μM. These data suggest that APINACA can cause drug interactions in the clinic via the inhibition of CYP3A4 or UGT1A9 activities. MDPI 2019-08-19 /pmc/articles/PMC6720883/ /pubmed/31430908 http://dx.doi.org/10.3390/molecules24163000 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kim, Sunjoo Choi, Won-Gu Kwon, Mihwa Lee, Sowon Cho, Yong-Yeon Lee, Joo Young Kang, Han Chang Song, Im-Sook Lee, Hye Suk In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters |
title | In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters |
title_full | In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters |
title_fullStr | In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters |
title_full_unstemmed | In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters |
title_short | In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters |
title_sort | in vitro inhibitory effects of apinaca on human major cytochrome p450, udp-glucuronosyltransferase enzymes, and drug transporters |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720883/ https://www.ncbi.nlm.nih.gov/pubmed/31430908 http://dx.doi.org/10.3390/molecules24163000 |
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