Abstract
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.
Highlights
Synthetic cannabinoids (SCs) are new psychoactive substances mimicking ∆9-tetrahydrocannabinol (THC), the active component of cannabis, and typically bind to the cannabinoid receptor type 1 (CB1)or type 2 (CB2) [1]
We investigated the in vitro inhibitory effects of AB-FUBINACA on the activities of eight major cytochrome P450s (CYPs) and six uridine -diphospho-glucuronosyltransferases (UGTs) of pooled human liver microsomes and on the transport activities of six solute carrier transporters and two efflux transporters of transporter-overexpressing cells, to predict potential AB-FUBINACA-induced drug–drug interactions (DDIs)
The reversible and time-dependent inhibitory effects (IC50 values) of AB-FUBINACA on eight major human CYP enzyme activities of ultrapooled human liver microsomes were evaluated using a cocktail of CYP substrates and liquid chromatography-tandem mass spectrometry (LC-MS/MS)
Summary
Synthetic cannabinoids (SCs) are new psychoactive substances mimicking ∆9-tetrahydrocannabinol (THC), the active component of cannabis, and typically bind to the cannabinoid receptor type 1 (CB1)or type 2 (CB2) [1]. Synthetic cannabinoids (SCs) are new psychoactive substances mimicking ∆9-tetrahydrocannabinol (THC), the active component of cannabis, and typically bind to the cannabinoid receptor type 1 (CB1). SC misuse has increased worldwide; 169 SCs are monitored by the European. Molecules 2020, 25, 4589 cannabinoid receptor type 1 (CB1) or type 2 (CB2) [1]. SC misuse has increased worldwide; 169 SCs are monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the EU Early Warning System established in December 2016. AB-FUBINACA was developed by Pfizer in 2009 as an analgesic drug candidate, but development was not pursued. The material was identified for the first time in Japanese herbal smoking blends in 2012 and has been included in Schedule I of the Controlled Substances Act by the US Drug Enforcement Administration since 2014
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