In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites

Abstract

The escalating use of medical cannabis and significant recreational use of cannabis in recent years has led to a higher potential for metabolic interactions between cannabis or one or more of its components and concurrently used medications. Although there have been a significant number of in vitro and in vivo assessments of the effects of cannabis on cytochrome P450 and UDP-glucuronosyltransferase enzyme systems, there is limited information regarding the effects of cannabis on the major hepatic esterase, carboxylesterase 1 (CES1). In this study, we investigated the in vitro inhibitory effects of the individual major cannabinoids and metabolites Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), 11-nor-THC-carboxylic acid, and 11-hydroxy-THC on CES1 activity. S9 fractions from human embryonic kidney 293 cells stably expressing CES1 were used in the assessment of cannabinoid inhibitory effects. THC, CBD, and CBN each exhibited substantial inhibitory potency, and were further studied to determine their mechanism of inhibition and kinetic parameters. The inhibition of CES1 by THC, CBD, and CBN was reversible and appears to proceed through a mixed competitivenoncompetitive mechanism. The inhibition constant (K i ) values for THC, CBD, and CBN inhibition were 0.541, 0.974, and 0.263 mM (0.170, 0.306, and 0.0817 mg/ml), respectively. Inhibition potency was increased when THC, CBD, and CBN were combined. Compared with the potential unbound plasma concentrations attainable clinically, the K i values suggest a potential for clinically significant inhibition of CES1 by THC and CBD. CBN, however, is expected to have a limited impact on CES1. Carefully designed clinical studies are warranted to establish the clinical significance of these in vitro findings.https://doi.org/10.1124/dmd.118.086074.ABBREVIATIONS: AUC, area under the plasma concentration-time curve; CBD, cannabidiol; CBN, cannabinol; CES1, carboxylesterase 1; DDI, drug-drug interaction; [I], inhibitor concentration; I max , maximal degree of inhibition; I max,u , maximal unbound plasma concentration of the inhibitor observed in clinical studies; K i , inhibition constant; LC-MS/MS, liquid chromatography tandem mass spectrometry; OC, oseltamivir carboxylate; 11-OH-THC, 11-hydroxy-Δ9-tetrahydrocannabinol; OST, oseltamivir phosphate; P450, cytochrome P450; R AUC , ratio of the area under plasma concentration-time curve of substrate with the presence of inhibitor over that without; R v , percentage ratio; THC, Δ9-tetrahydrocannabinol; THC-COOH, 11-nor-Δ9-tetrahydrocannabinol-carboxylic acid; UGT, UDP-glucuronosyltransferase.

Cannabidiol Protects Dopaminergic Neurons in Mesencephalic Cultures against the Complex I Inhibitor Rotenone Via Modulation of Heme Oxygenase Activity and Bilirubin

“…The reduced heme converting capacity in the presence of CBs might be the consequence of direct interaction with the enzyme in analogy to the (previously described) inhibition of cytochrome P450 isoenzymes in-vitro by CBD [67][68][69]. We, therefore, checked whether CBs are able to interfere with the HO reaction in-vitro directly.…”

Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators

“…An in vitro study with CES1-transfected cells suggested that cannabis [i.e., tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN)] can act as a potential CES1 inhibitor. The inhibition constant (Ki) values for THC, CBD, and CBN were 0.541, 0.974, and 0.263 mM (0.170, 0.306, and 0.0817 mg/ml), respectively (Qian et al, 2019). This result could be clinically impactful because the use of cannabis is expected to increase in the next few years (Hasin, 2018).…”

Potential Adverse Drug Events with Tetrahydrocannabinol (THC) Due to Drug–Drug Interactions

“…THC has been shown to have broad inhibitory effects on CYP450 enzymes including CYP3A, CYP2D6, CYP2C9, CYP2C19, CYP2A6, CYP2B6, CYP1A1/2, and CYP2J2 [39]. In addition, new evidence suggests that cannabinoids, including THC, have strong inhibitory effects on carboxylesterase 1 (CES1), which is important in the metabolism of many medications [39][40][41]. Overall, THC is less implicated in DDIs compared to CBD, but is still likely to contribute to this risk at clinically relevant concentrations.…”