AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes
AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhi...
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doaj-29d2d26c13e842b9984b4d1ca601b4032020-11-24T23:14:29ZengMDPI AGMolecules1420-30492017-03-0122344310.3390/molecules22030443molecules22030443AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver MicrosomesJu-Hyun Kim0Soon-Sang Kwon1Tae Yeon Kong2Jae Chul Cheong3Hee Seung Kim4Moon Kyo In5Hye Suk Lee6Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, KoreaDrug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, KoreaDrug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, KoreaForensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor’s Office, 157 Banpo-daero, Seocho-gu, Seoul 06590, KoreaForensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor’s Office, 157 Banpo-daero, Seocho-gu, Seoul 06590, KoreaForensic Chemistry Laboratory, Forensic Science Division, Supreme Prosecutor’s Office, 157 Banpo-daero, Seocho-gu, Seoul 06590, KoreaDrug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, KoreaAM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) enzymes in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry to investigate drug interaction potentials of AM-2201. AM-2201 potently inhibited CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP3A4-catalyzed midazolam 1′-hydroxylation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, and UGT2B7-catalyzed naloxone 3-glucuronidation with IC50 values of 3.9, 4.0, 4.3, and 10.0 μM, respectively, and showed mechanism-based inhibition of CYP2C8-catalyzed amodiaquine N-deethylation with a Ki value of 2.1 μM. It negligibly inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, and UGT1A9 activities at 50 μM in human liver microsomes. These in vitro results indicate that AM-2201 needs to be examined for potential pharmacokinetic drug interactions in vivo due to its potent inhibition of CYP2C8, CYP2C9, CYP3A4, UGT1A3, and UGT2B7 enzyme activities.http://www.mdpi.com/1420-3049/22/3/443AM-2201cytochrome P450 inhibitionUDP-glucuronosyltransferase inhibitionhuman liver microsomesdrug-drug interaction |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ju-Hyun Kim Soon-Sang Kwon Tae Yeon Kong Jae Chul Cheong Hee Seung Kim Moon Kyo In Hye Suk Lee |
spellingShingle |
Ju-Hyun Kim Soon-Sang Kwon Tae Yeon Kong Jae Chul Cheong Hee Seung Kim Moon Kyo In Hye Suk Lee AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes Molecules AM-2201 cytochrome P450 inhibition UDP-glucuronosyltransferase inhibition human liver microsomes drug-drug interaction |
author_facet |
Ju-Hyun Kim Soon-Sang Kwon Tae Yeon Kong Jae Chul Cheong Hee Seung Kim Moon Kyo In Hye Suk Lee |
author_sort |
Ju-Hyun Kim |
title |
AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes |
title_short |
AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes |
title_full |
AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes |
title_fullStr |
AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes |
title_full_unstemmed |
AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5′-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes |
title_sort |
am-2201 inhibits multiple cytochrome p450 and uridine 5′-diphospho-glucuronosyltransferase enzyme activities in human liver microsomes |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2017-03-01 |
description |
AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) enzymes in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry to investigate drug interaction potentials of AM-2201. AM-2201 potently inhibited CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP3A4-catalyzed midazolam 1′-hydroxylation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, and UGT2B7-catalyzed naloxone 3-glucuronidation with IC50 values of 3.9, 4.0, 4.3, and 10.0 μM, respectively, and showed mechanism-based inhibition of CYP2C8-catalyzed amodiaquine N-deethylation with a Ki value of 2.1 μM. It negligibly inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, and UGT1A9 activities at 50 μM in human liver microsomes. These in vitro results indicate that AM-2201 needs to be examined for potential pharmacokinetic drug interactions in vivo due to its potent inhibition of CYP2C8, CYP2C9, CYP3A4, UGT1A3, and UGT2B7 enzyme activities. |
topic |
AM-2201 cytochrome P450 inhibition UDP-glucuronosyltransferase inhibition human liver microsomes drug-drug interaction |
url |
http://www.mdpi.com/1420-3049/22/3/443 |
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