Inhibition of cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferases by MAM-2201 in human liver microsomes

Kong, Tae Yeon; Kim, Ju-Hyun; Kwon, Soon-Sang; Cheong, Jae Chul; Kim, Hee Seung; In, Moon Kyo; Lee, Hye Suk

doi:10.1007/s12272-017-0917-y

Cited by 11 publications

(18 citation statements)

References 46 publications

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“…AB-FUBINACA competitively inhibited CYP2C8-catalyzed amodiaquine N -de-ethylation and CYP2C9-mediated diclofenac 4′-hydroxylation with K i values of 19.9 and 13.1 μM, respectively: other synthetic cannabinoids including AM-2201, EAM-2201, and MAM-2201 potently inhibited CYP2C8-catalyzed amodiaquine N -de-ethylation ( K i , 0.54–2.1 µM) and CYP2C9-mediated diclofenac 4′-hydroxylation ( K i , 3.0–5.6 µM) by ultrapooled human liver microsomes [ 27 , 28 , 29 ]. AB-FUBINACA exhibited mixed inhibition of CYP2B6-mediated bupropion hydroxylation with a K i of 15.0 μM.…”

Section: Discussionmentioning

confidence: 99%

“…AM-2201 ( K i , 4.0 µM), MAM-2201 ( K i , 5.4 µM), EAM-2201 ( K i , 4.1 μM and k inact , 0.0250 min −1 ), and APINACA ( K i , 4.5 µM; k inact , 0.04686 min −1 ) inhibited CYP3A4-catalyzed midazolam 1′-hydroxylation in human liver microsomes [ 27 , 28 , 29 , 30 ], but AB-FUBINACA did not inhibit the CYP3A4, CYP1A2, and CYP2A6 activities of such microsomes ( Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…AB-FUBINACA negligibly inhibited the UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 activities of human liver microsomes, suggesting that the risk of clinical DDIs between AB-FUBINACA and the UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 metabolizing enzymes is remote. However, EAM-2201, MAM-2201, and AM-2201 competitively inhibited UGT1A3-mediated chenodeoxycholic acid 24-acyl-β-glucuronidation with K i values of 2.7, 4.3, and 5.0 μM, respectively, and APINACA noncompetitively inhibited UGT1A9-mediated mycophenolic acid glucuronidation ( K i , 5.9 µM) by human liver microsomes [ 27 , 28 , 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…The inhibitory potentials (IC 50 values) of AB-FUBINACA on CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 activities in pooled human liver microsomes were evaluated using a slight modification of our previously described method that employed a cocktail of CYP substrates, followed by LC-MS/MS [ 27 , 28 , 29 , 30 ]. The incubation mixtures were prepared in total volumes of 100 μL as follows: 50 mM potassium phosphate buffer (pH 7.4), 1.0 mM NADPH, 10 mM MgCl 2 , ultrapooled human liver microsomes (0.2 mg/mL), various concentrations of AB-FUBINACA (final concentrations of 0.1–100 μM), and the CYP enzyme-specific substrates of the cocktail sets A (2.0 μM amodiaquine, 5 μM bufuralol, 2.5 μM coumarin, 10 μM diclofenac, 100 μM [ S ]-mephenytoin, 2.5 μM midazolam, and 50 μM phenacetin) and B (50 μM bupropion).…”

Section: Methodsmentioning

confidence: 99%

“…Drug abusers frequently take several drugs concomitantly [ 13 , 14 , 15 ]; it is thus necessary to investigate the inhibitory effects of drugs on major drug-metabolizing enzymes such as cytochrome P450s (CYPs) and 5′-diphospho-glucuronosyltransferases (UGTs); and on clinically important drug transporters such as solute carrier transporters including the organic cation transporters (OCT)1, and OCT2, the organic anion transporters (OAT)1 and OAT3, the organic anion transporting polypeptides (OATP)1B1 and OATP1B3, and efflux transporters such as P-glycoprotein (P-gp) and breast cancer-resistance protein (BCRP) [ 16 , 17 , 18 ]. The inhibitory effects of phytocannabinoids including THC, cannabinol, cannabidiol [ 19 , 20 , 21 , 22 , 23 , 24 , 25 ], and synthetic cannabinoids (JWH-019, STS-135, UR-144, AM-2201, MAM-2201, EAM-2201, and APINACA) [ 4 , 26 , 27 , 28 , 29 , 30 ], on the major CYP and UGT enzymes or human liver microsomes, or recombinant CYP and UGT enzymes, have been reported [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Interaction of AB-FUBINACA with Human Cytochrome P450, UDP-Glucuronosyltransferase Enzymes and Drug Transporters

Kim

Shin

et al. 2020

Molecules

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AB-FUBINACA, a synthetic indazole carboxamide cannabinoid, has been used worldwide as a new psychoactive substance. Because drug abusers take various drugs concomitantly, it is necessary to explore potential AB-FUBINACA-induced drug–drug interactions caused by modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of AB-FUBINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) of human liver microsomes, and on eight clinically important transport activities including organic cation transporters (OCT)1 and OCT2, organic anion transporters (OAT)1 and OAT3, organic anion transporting polypeptide transporters (OATP)1B1 and OATP1B3, P-glycoprotein, and breast cancer resistance protein (BCRP) in transporter-overexpressing cells were investigated. AB-FUBINACA inhibited CYP2B6-mediated bupropion hydroxylation via mixed inhibition with Ki value of 15.0 µM and competitively inhibited CYP2C8-catalyzed amodiaquine N-de-ethylation, CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4′-hydroxylation, and CYP2D6-catalyzed bufuralol 1′-hydroxylation with Ki values of 19.9, 13.1, 6.3, and 20.8 µM, respectively. AB-FUBINACA inhibited OCT2-mediated MPP+ uptake via mixed inhibition (Ki, 54.2 µM) and competitively inhibited OATP1B1-mediated estrone-3-sulfate uptake (Ki, 94.4 µM). However, AB-FUBINACA did not significantly inhibit CYP1A2, CYP2A6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B7 enzyme activities at concentrations up to 100 µM. AB-FUBINACA did not significantly inhibit the transport activities of OCT1, OAT1/3, OATP1B3, P-glycoprotein, or BCRP at concentrations up to 250 μM. As the pharmacokinetics of AB-FUBINACA in humans and animals remain unknown, it is necessary to clinically evaluate potential in vivo pharmacokinetic drug–drug interactions induced by AB-FUBINACA-mediated inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, OCT2, and OATP1B1 activities.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Vitro Interaction of AB-FUBINACA with Human Cytochrome P450, UDP-Glucuronosyltransferase Enzymes and Drug Transporters

Kim

Shin

et al. 2020

Molecules

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MAM-2201 acute administration impairs motor, sensorimotor, prepulse inhibition, and memory functions in mice: a comparison with its analogue AM-2201

et al. 2023

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Rationale 1-[(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl) methanone (MAM-2201) is a potent synthetic cannabinoid receptor agonist illegally marketed in “spice” products and as “synthacaine” for its psychoactive effects. It is a naphthoyl-indole derivative which differs from its analogue 1-[(5-Fluoropentyl)-1H-indol-3-yl](1-naphthylenyl) methanone (AM-2201) by the presence of a methyl substituent on carbon 4 (C-4) of the naphthoyl moiety. Multiple cases of intoxication and impaired driving have been linked to AM-2201 and MAM-2201 consumption. Objectives This study aims to investigate the in vitro (murine and human cannabinoid receptors) and in vivo (CD-1 male mice) pharmacodynamic activity of MAM-2201 and compare its effects with those induced by its desmethylated analogue, AM-2201. Results In vitro competition binding studies confirmed that MAM-2201 and AM-2201 possess nanomolar affinity for both CD-1 murine and human CB1 and CB2 receptors, with preference for the CB1 receptor. In agreement with the in vitro binding data, in vivo studies showed that MAM-2201 induces visual, acoustic, and tactile impairments that were fully prevented by pretreatment with CB1 receptor antagonist/partial agonist AM-251, indicating a CB1 receptor mediated mechanism of action. Administration of MAM-2201 also altered locomotor activity and PPI responses of mice, pointing out its detrimental effect on motor and sensory gating functions and confirming its potential use liability. MAM-2201 and AM-2201 also caused deficits in short- and long-term working memory. Conclusion These findings point to the potential public health burden that these synthetic cannabinoids may pose, with particular emphasis on impaired driving and workplace performance.

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Interaction between phytotherapy and oral anticancer agents: prospective study and literature review

et al. 2019

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Inhibition of cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferases by MAM-2201 in human liver microsomes

Cited by 11 publications

References 46 publications

In Vitro Interaction of AB-FUBINACA with Human Cytochrome P450, UDP-Glucuronosyltransferase Enzymes and Drug Transporters

In Vitro Interaction of AB-FUBINACA with Human Cytochrome P450, UDP-Glucuronosyltransferase Enzymes and Drug Transporters

MAM-2201 acute administration impairs motor, sensorimotor, prepulse inhibition, and memory functions in mice: a comparison with its analogue AM-2201

Interaction between phytotherapy and oral anticancer agents: prospective study and literature review

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