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Inhibitory Effect of AB-PINACA, Indazole Carboxamide Synthetic Cannabinoid, on Human Major Drug-Metabolizing Enzymes and Transporters

Authors :
Eun Jeong Park
Ria Park
Ji-Hyeon Jeon
Yong-Yeon Cho
Joo Young Lee
Han Chang Kang
Im-Sook Song
Hye Suk Lee
Source :
Pharmaceutics, Vol 12, Iss 11, p 1036 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

Indazole carboxamide synthetic cannabinoid, AB-PINACA, has been placed into Schedule I of the Controlled Substances Act by the US Drug Enforcement Administration since 2015. Despite the possibility of AB-PINACA exposure in drug abusers, the interactions between AB-PINACA and drug-metabolizing enzymes and transporters that play crucial roles in the pharmacokinetics and efficacy of various substrate drugs have not been investigated. This study was performed to investigate the inhibitory effects of AB-PINACA on eight clinically important human major cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGT) in human liver microsomes and the activities of six solute carrier transporters and two efflux transporters in transporter-overexpressing cells. AB-PINACA reversibly inhibited the metabolic activities of CYP2C8 (Ki, 16.9 µM), CYP2C9 (Ki, 6.7 µM), and CYP2C19 (Ki, 16.1 µM) and the transport activity of OAT3 (Ki, 8.3 µM). It exhibited time-dependent inhibition on CYP3A4 (Ki, 17.6 µM; kinact, 0.04047 min−1). Other metabolizing enzymes and transporters such as CYP1A2, CYP2A6, CYP2B6, CYP2D6, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, OAT1, OATP1B1, OATP1B3, OCT1, OCT2, P-glycoprotein, and BCRP, exhibited only weak interactions with AB-PINACA. These data suggest that AB-PINACA can cause drug-drug interactions with CYP3A4 substrates but that the significance of drug interactions between AB-PINACA and CYP2C8, CYP2C9, CYP2C19, or OAT3 substrates should be interpreted carefully.

Details

Language :
English
ISSN :
19994923
Volume :
12
Issue :
11
Database :
Directory of Open Access Journals
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
edsdoj.2911d11a4ca64a1e93f8d928370ee011
Document Type :
article
Full Text :
https://doi.org/10.3390/pharmaceutics12111036