A systematic study of the in vitro pharmacokinetics and estimated human in vivo clearance of indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists detected on the illicit drug market

Brandon, A. M., Antonides, L. H., Riley, J., Epemolu, O., McKeown, D. A., Read, K. D. and McKenzie, C. (2021) A systematic study of the in vitro pharmacokinetics and estimated human in vivo clearance of indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists detected on the illicit drug market. Molecules, 26(5), 1396. (doi: 10.3390/molecules26051396) (PMID:33807614) (PMCID:PMC7961380)

Abstract

In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D7.4 ranged from 2.81 (AB-FUBINACA) to 4.95 (MDMB-4en-PINACA) and all SCRAs tested were highly protein bound, ranging from 88.9 ± 0.49% ((R)-4F-MDMB-BINACA) to 99.5 ± 0.08% ((S)-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CLint) ranged from 13.7 ± 4.06 ((R)-AB-FUBINACA) to 2944 ± 95.9 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 ((S)-AB-FUBINACA) to 3216 ± 607 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CLH) ranged from 0.34 ± 0.09 ((S)-AB-FUBINACA) to 17.79 ± 0.20 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 ((S)-MDMB-FUBINACA) to 18.25 ± 0.12 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHHeps. Valinate and tert-leucinate indole and indazole-3-carboxamide SCRAs are often rapidly metabolised in vitro but are highly protein bound in vivo and therefore predicted in vivo CLH is much slower than CLint. This is likely to give rise to longer detection windows of these substances and their metabolites in urine, possibly as a result of accumulation of parent drug in lipid-rich tissues, with redistribution into the circulatory system and subsequent metabolism.

• Item Type: Articles
• Additional Information: This research and the APC was funded by the Engineering and Physical Sciences Research Council (EPSRC) Doctoral Training Partnership, Grant Number EP/N509962/1. The Leverhulme Research Centre for Forensic Science (LRCFS) is funded by the Leverhulme Trust, Grant Number RC-2015-01.
• Keywords: New psychoactive substances, synthetic cannabinoid receptor agonists, in vitro metabolism, in vivo prediction, pharmacokinetics.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mckeown, Miss Denise

Creator Roles

McKeown, D. A.: Writing – review and editing, Supervision

• Authors: Brandon, A. M., Antonides, L. H., Riley, J., Epemolu, O., McKeown, D. A., Read, K. D., and McKenzie, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• ISSN (Online): 1420-3049
• Published Online: 05 March 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Molecules 26(5): 1396
• Publisher Policy: Reproduced under a Creative Commons License