In Vitro Inhibitory Effects of APINACA on Human Major Cytochrome P450, UDP-Glucuronosyltransferase Enzymes, and Drug Transporters

• Main Authors: Sunjoo Kim, Won-Gu Choi, Mihwa Kwon, Sowon Lee, Yong-Yeon Cho, Joo Young Lee, Han Chang Kang, Im-Sook Song, Hye Suk Lee
• Format: Article
• Language: English
• Published: MDPI AG 2019-08-01
• Series: Molecules
• Subjects: APINACA; drug–drug interaction; cytochrome P450; uridine 5′-diphospho-glucuronosyltransferases; drug transporters
• Online Access: https://www.mdpi.com/1420-3049/24/16/3000

APINACA (known as AKB48, <i>N</i>-(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&#8722;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&#8242;-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&#8242;-hydroxylation (<i>K_i</i>, 4.5 &#181;M; <i>k_inact</i>, 0.04686 min^&#8722;1) and noncompetitive inhibition of UGT1A9-mediated mycophenolic acid glucuronidation (<i>K_i</i>, 5.9 &#181;M). 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 &#181;M. 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 &#956;M. These data suggest that APINACA can cause drug interactions in the clinic via the inhibition of CYP3A4 or UGT1A9 activities.