Kopjar_2020_Clin.Drug.Investig_40_775

This review proposes the hypothesis that the effectiveness of irinotecan chemotherapy might be impaired by high doses of concomitantly administered delta(9)-tetrahydrocannabinol (THC). The most important features shared by irinotecan and THC, which might represent sources of potentially harmful interactions are: first-pass hepatic metabolism mediated by cytochrome P450 (CYP) enzyme CYP3A4; glucuronidation mediated by uridine diphosphate glycosyltransferase (UGT) enzymes, isoforms 1A1 and 1A9; transport of parent compounds and their metabolites via canalicular ATP-binding cassette (ABC) transporters ABCB1 and ABCG2; enterohepatic recirculation of both parent compounds, which leads to an extended duration of their pharmacological effects; possible competition for binding to albumin; butyrylcholinesterase (BChE) inhibition by THC, which might impair the conversion of parent irinotecan into the SN-38 metabolite; mutual effects on mitochondrial dysfunction and induction of oxidative stress; potentiation of hepatotoxicity; potentiation of genotoxicity and cytogenetic effects leading to genome instability; possible neurotoxicity; and effects on bilirubin. The controversies associated with the use of highly concentrated THC preparations with irinotecan chemotherapy are also discussed. Despite all of the limitations, the body of evidence provided here could be considered relevant for human-risk assessments and calls for concern in cases when irinotecan chemotherapy is accompanied by preparations rich in THC.