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.

In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or -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 D 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% (()-4F-MDMB-BINACA) to 99.5 ± 0.08% (()-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CL) ranged from 13.7 ± 4.06 (()-AB-FUBINACA) to 2944 ± 95.9 mL min kg (()-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 (()-AB-FUBINACA) to 3216 ± 607 mL min kg (()-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CL) ranged from 0.34 ± 0.09 (()-AB-FUBINACA) to 17.79 ± 0.20 mL min kg (()-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 (()-MDMB-FUBINACA) to 18.25 ± 0.12 mL min kg (()-5F-AMB-PINACA) in pHHeps. Valinate and -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 CL is much slower than CL. 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.