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Interactions between cannabinoids and anticancer drugs: an example of Δ9-tetrahydrocannabinol and irinotecan

The global use of preparations based on Cannabis sativa, both prescribed and illicit, is increasing among cancer patients. Generally, drug-drug or herb-drug interactions can result in therapeutic failure and it has been estimated to be the cause of death in approximately 4% of cancer patients. Interactions of cannabinoids with conventional chemotherapeutics are still poorly recognized. Irinotecan (IRI) is an anticancer drug whose use may lead to severe toxicities (predominantly neutropenia and diarrhoea) that require co-medications. The main active constituent of C. sativa, delta-9- tetrahydrocannabinol (THC), possesses a wide range of pharmacologic effects that might be of therapeutic benefit during therapy with IRI but its adverse psychotropic effects, as well as unknown toxic effects, must be borne in mind. Furthermore, there is a complex overlapping between IRI and THC metabolic pathways: both compounds are subject to the first pass hepatic metabolism mediated by the CYP3A4 enzyme ; their metabolites are subject to glucuronidation via the UGT1A1 enzyme ; the transport of parent compounds and their metabolites depends on the same or related transporters ; both compounds are subject to enterohepatic recirculation ; both compounds bind to plasma proteins ; both compounds affect mitochondrial oxidative phosphorylation and fatty acids metabolism. We present the results of a pilot study conducted on healthy male Wistar rats as a preliminary assessment of IRI and THC interactions. The experimental schedule included a single intraperitoneal application of IRI (at 100 mg/kg), while THC was administered per os repeatedly for 1, 3, and 7 days (at 7 mg/kg). The concomitant use of THC with IRI caused a prominent body and liver weight reduction and affected several clinical chemistry parameters in rats. Enhanced urinary THC excretion in animals treated with THC and IRI was noticed compared to THC alone. THC intake caused a significant synergic enhancement of IRI genotoxicity and oxidative stress responses.

Delta-9-tetrahydrocannabinol ; irinotecan ; interactions ; rats

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