Abstract
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 (Ki, 4.5 µM; kinact, 0.04686 min−1) and noncompetitive inhibition of UGT1A9-mediated mycophenolic acid glucuronidation (Ki, 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.
Highlights
Synthetic cannabinoids (SCs) are a type of new psychoactive substance that mimic∆9-tetrahydrocannabinol (THC), the active component of cannabis, and typically bind to cannabinoid receptor type 1 or type 2 [1]
APINACA was identified for the first time in Japanese herbal smoking blends in 2012 and has been categorized in Schedule I of the Controlled Substances Act
The inhibitory potentials of typical cytochrome P450s (CYPs) inhibitors were evaluated in ultrapooled human liver microsomes, as follows: α-naphthoflavone (IC50, 0.06 μM), sulfaphenazole (IC50, 0.8 μM)
Summary
Synthetic cannabinoids (SCs) are a type of new psychoactive substance that mimic∆9-tetrahydrocannabinol (THC), the active component of cannabis, and typically bind to cannabinoid receptor type 1 or type 2 [1]. Synthetic cannabinoids (SCs) are a type of new psychoactive substance that mimic. APINACA (known as AKB48, N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide) is an SC classified as an indazole carboxamide (Figure 1) [2]. APINACA was identified for the first time in Japanese herbal smoking blends in 2012 and has been categorized in Schedule I of the Controlled Substances Act. Molecules 2019, 24, 3000; doi:10.3390/molecules24163000 www.mdpi.com/journal/molecules. Molecules 2019, 24, x FOR PEER REVIEW by the US Drug Enforcement Administration since 2013. Substances Act by the US Drug Enforcement Administration since 2013. APINACA is extensively metabolites in vitro and in vivo via hydroxylation and oxidation at pentyl and adamantyl moieties by metabolized to 10 metabolites in vitro and in vivo via hydroxylation and oxidation at pentyl and cytochrome
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