In VitroScreening of Three Commercial Cannabis-Based Products on ATP-Binding Cassette and Solute-Carrier Transporter Function

Abstract

Introduction: Legalization of medicinal cannabis around the world has led to an increase in the use of commercial cannabis-based products in the community. These cannabis-based products are being used in combination with conventional drugs to treat a variety of health conditions. Moreover, recreational cannabis-based products may be used in combination with other drugs. In this setting, there is increased potential for drug-drug interactions (DDIs) involving commercial cannabis-based products. Since DDIs can lead to serious adverse events, drug regulatory bodies require that every investigational drug be evaluated for DDI potential at metabolic enzymes and transporters. However, this seldom occurs for cannabis-based products due to legislation in many jurisdictions allowing a direct pathway to market. This study aimed to examine the inhibitory potential of three commercially available cannabis-based products at human ATP-binding cassette (ABC) and solute-carrier (SLC) transporters. Materials and Methods: Three commercial cannabis-based products (Spectrum YellowÔ, Tweed Argyle, and Spectrum RedÔ) that contain differing concentrations of cannabidiol (CBD) and D 9-tetrahydrocannabinol (D 9-THC) were evaluated for DDI potential at 12 drug transporters. HEK293 cells or vesicles expressing human ABC transporters (ABCB1, ABCC2, ABCG2, or ABCB11) and SLC transporters (SLC22A1, SLC22A2, SLC22A6, SLC22A8, SLCO1B1, SLCO1B3, SLC47A1, and SLC47A2) were used to measure transporter function. Results: Spectrum Yellow and Tweed Argyle inhibited ABCG2 transporter function. The IC 50 value of Spectrum Yellow based on CBD and D 9-THC content was 4.5 lM for CBD and 0.20 lM for D 9-THC, and the IC 50 value of Tweed Argyle was 9.3 lM for CBD and 6.0 lM for D 9-THC. Tweed Argyle also inhibited ABCB11 transporter function with an IC 50 value of 11.9 lM for CBD and 7.7 lM for D 9-THC. SLC22A6, SLC22A1, SLC22A2, SLCO1B1, and SLCO1B3 transporter functions were modestly inhibited by high concentrations of the cannabis-based products. The three cannabis-based products did not inhibit ABCB1, ABCC2, SLC47A1, SLC47A2, or SLC22A8 transporters. Discussion: Novel findings were that the cannabis-based products inhibited ABCB11, SLC22A6, SLC22A1, SLC22A2, SLCO1B1, and SLCO1B3 (although modestly in most instances). Spectrum Yellow and Tweed Argyle potently inhibited ABCG2, and future in vivo DDI studies could be conducted to assess whether cannabis products affect the pharmacokinetics of medications that are ABCG2 substrates.

Cannabis constituents interact at the drug efflux pump BCRP to markedly increase plasma cannabidiolic acid concentrations

“…The best characterised ABC transporters, P-glycoprotein and breast cancer resistance protein (BCRP), are located on the apical surface of epithelial cells in the intestine and extrude substrates back into the intestinal lumen, thereby limiting systemic absorption. Cannabinoids are both substrates and/or inhibitors of ABC transporters so we aimed to examine whether the converging action of the cannabinoids on these transporters might provide a mechanism for the pharmacokinetic interaction observed here 15 – 19 .…”

“…We also determined whether the cannabinoids were inhibitors of BCRP and P-glycoprotein. Previous in vitro and ex vivo studies reported that CBD, Δ 9 -THC and cannabis-based products inhibit BCRP 17 – 19 . Consistent with these previous studies, CBD inhibited BCRP-mediated transport of prazosin.…”

Clinical Pharmacology of Cannabinoid Therapeutics: Drug Interactions and Side Effects

“…The terminal half‐life of THC in plasma is ~22 hours 8 . According to in vitro studies, THC is substrate of the ABC‐transporter P‐glycoprotein (ABCB1) and BCRP (ABCG2) and inhibits these only weakly 9 . Studies on the placental transfer of THC and COOH‐THC, however, reported no difference in transport after inhibition of P‐gp/BCRP by valspodar 7 …”

“…8 According to in vitro studies, THC is substrate of the ABC-transporter P-glycoprotein (ABCB1) and BCRP (ABCG2) and inhibits these only weakly. 9 Studies on the placental transfer of THC and COOH-THC, however, reported no difference in transport after inhibition of P-gp/BCRP by valspodar. 7 The very lipophilic CBD is also strongly metabolized in the liver predominantly by CYP2C19 and slightly by CYP2C9 to 7-OH-CBD, which is further inactivated by CYP3A4 to the inactive 7-COOH-CBD.…”