Physiologically based pharmacokinetic modeling and simulation of cannabinoids in human plasma and tissues

Abstract

There has been an increased public interest in developing consumer products containing nonintoxicating cannabinoids, such as cannabidiol (CBD) and cannabigerol (CBG). At the present time, there is limited information available on the pharmacokinetics of cannabinoids in humans. Since pharmacokinetic profiles are important in understanding the pharmacological and toxicological effects at the target sites, physiologically based pharmacokinetic (PBPK) modeling was used to predict the plasma and tissue concentrations of 17 cannabinoids in humans. PBPK models were established using measured (in vitro) and predicted (in silico) physicochemical and pharmacokinetic properties, such as water solubility and effective human jejunal permeability. Initially, PBPK models were established for CBD and the model performance was evaluated using reported clinical data after intravenous and oral administration. PBPK models were then developed for 16 additional cannabinoids including CBG, and the plasma and tissue concentrations were predicted after 30 mg oral administration. The pharmacokinetic profiles of the 16 cannabinoids were similar to CBD, and the plasma concentration and time profiles of CBD agreed well with clinical data in the literature. Although low exposure was predicted in the plasma (maximum plasma concentrations < 15 nM), the predicted tissue concentrations, especially the liver (maximum liver concentrations 70-183 nM), were higher after oral administration of 30 mg cannabinoids. These predicted plasma and tissue concentrations could be used to guide further in vitro and in vivo testing.

Predicting binding between 55 cannabinoids and 4,799 biological targets by in silico methods

“…For example, orally administered CBD (grams per person per day) yields a C max near 1,000 nM, whereas for Δ9‐THC (milligrams per person per day), C max is near 50 nM. Additionally, several cannabinoids (30 mg doses) were predicted to yield plasma and tissue concentrations of 50–200 nM (Liu & Sprando, 2023). In this study, most quantitative binding predictions (209/311) yielded XC 50 < 1,000 nM, which lie in a more physiologically relevant concentration range worthy for further study.…”

Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity

“…Liu et al outlined a PBPK model to predict the PK profiles of 17 cannabinoids using in vitro and in silico predicted values for physicochemical properties (Liu and Sprando, 2022). In contrast to prior studies, this PBPK model predicted CBD concentrations in both plasma and major organs.…”

Prediction of physicochemical and pharmacokinetic properties of botanical constituents by computational models

“…In silico modeling, such as quantitative structure–activity relationships (QSAR) and physiologically based pharmacokinetic (PBPK) modeling and simulation, is an important tool to evaluate various chemicals, including drugs, food substances, and environmental compounds (Alqahtani, 2017; Bell et al, 2018; Pinto et al, 2016; Reddy et al, 2023). The application of in silico modeling in botanical assessment is increasing, and successful case studies have been published, such as QSAR modeling of physicochemical properties and toxicities (Liu, 2018) and PBPK simulation of plasma and tissue concentrations in humans (Liu & Sprando, 2023). These in silico methods have emerged as rapid means for screening, prioritizing more in‐depth studies, and filling data gaps for safety assessment.…”