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

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.

Herb–Drug Interaction of Red Ginseng Extract and Ginsenoside Rc with Valsartan in Rats

“…Rifampin inhibited OATP1B1 and OATP1B3 with IC 50 values of 28.6 µM and 0.81 µM, respectively. The results were comparable with IC 50 values of TEA reported in the literature (i.e., 1.4-7.4 mM for OCT1 and 2.05 mM for OCT2; 7.6 µM for OAT1 and 4.1 µM for OAT3; 0.8-22.8 µM for OATP1B1 and 0.8-6.4 µM for OATP1B3[24][25][26][27][28].…”

“…In the inhibition studies, the uptake rate of substrate by HEK293 cells overexpressing the respective transporters was used as the control (100%) and the uptake rate of substrates in the presence of typical inhibitors or ginsenosides expressed as a percentage of the control. The inhibition data were fitted to an inhibitory effect model [26] using Sigma plot (version 10.0; Systat Software Inc., San Jose, CA, USA). IC 50 value indicated the half-maximal inhibitory concentration of the inhibitor.…”

“…HEK293 cells overexpressing the OCT1, OCT2, OAT1, OAT3, OATP1B1, and OATP1B3 transporters (HEK293-OCT1, -OCT2, -OAT1, -OAT3, -OATP1B1, and -OATP1B3, respectively) and HEK293-mock cells (Corning Life Sciences; Woburn, MA, USA) were used and characterized as previously described [26,45,46].…”

Comparative Pharmacokinetics and Pharmacodynamics of a Novel Sodium-Glucose Cotransporter 2 Inhibitor, DWP16001, with Dapagliflozin and Ipragliflozin

“…To investigate the mode of inhibition of the three SGLT2 inhibitors, the inhibition experiments were initiated by replacing Na + -free buffer with Na + gradient buffer containing 1, 2.5, 5, and 50 µM [ 14 C]AMG and various concentrations of DWP16001, dapagliflozin, or ipragliflozin (0.001 nM-250 nM) and the uptake of [ 14 C]AMG into the CHO-mock and -SGLT2 cells was measured for 2 h. The radioactivity of the cell lysate was measured following the same sample preparation method described above. Uptake rate of AMG and concentrations of DWP16001, dapagliflozin, or ipragliflozin were plotted to Dixon plots to identify the mode of inhibition [13,14].…”

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

“…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 ].…”