Table 7.

Cannabinoid interactions with drug transporters.

Cannabinoids as substrates for efflux transporters
Transporter	Cannabinoid	Dose or Concentration	Experimental system(s)	Key observations	Reference
P-gp	THC	25 mg/kg (oral)	Mice	2× higher AUC in CF1 (P-gp-deficient) mice compared to wild type mice	(Bonhomme-Faivre et al., 2008)
	THC	3 mg/kg (ip)	Mice	1.5-4.2× higher brain/blood THC ratio in Abcb1a/b(−/−)(−/−) mice compared to wild type mice	(Spiro et al., 2012)
	CBD	10 mg/kg (sc)	Mice	Brain/blood CBD ratio in Abcb1a/b(−/−) mice was not different from that in wild type mice	(Brzozowska et al., 2016)
	CBN	1-100 μM	Human P-gp membranes	P-gp ATPase activity was stimulated, with CIint = 0.7 min−1 × 10−3	(Zhu et al., 2006)
Bcrp	THC	3 mg/kg (ip)	Mice	1.9-6.1× higher brain/blood THC ratio in Abcg2(−/−) mice compared to wild type mice	(Spiro et al., 2012)
	CBD	10 mg/kg (sc)		Brain/blood CBD ratio was similar between Abcg2(−/−) and wild type mice	(Brzozowska et al., 2016)
Cannabinoids as inhibitors of efflux transporters
Transporter	Cannabinoid	Probe Substrate	Experimental system(s)	Key observations	Reference
P-gp	THC, CBD, CBN	Rhodamine 123	Human CEM/VLB100 cells	No increase in rhodamine 123 accumulation in the presence of cannabinoid (10 μM) after a 1-hour exposure	(Holland et al., 2006)
	CBD	Verapamil, Rhodamine 123	Human P-gp membranes; LLC-PK1/MDRI cells	IC50 = 39.6 μM for verapamil-stimulated P-gp ATPase activity in human P-gp membranes IC50= 8.44 ± 0.58 μM for rhodamine 123 accumulation in LLC-PK1/MDRI cells	(Zhu et al., 2006)
	THC, CBN	Verapamil	Human P-gp membranes	No inhibition of P-gp ATPase activity	(Zhu et al., 2006)
	THC	Risperidone, Clozapine	Mice	Decreased brain accumulation of risperidone (~25-50%) and 9-OH-risperidone (~33-63%) in mice treated with 1 mg/kg THC ip for 14 days followed by a 14-day wash-out. Repeated THC exposure did not impact clozapine (a non P-gp substrate) neurobehavioral effects.	(Brzozowska et al., 2017)
BCRP/Bcrp	THC, CBD, CBN	Sulfasalazine, Mitoxantrone	Human BCRP membranes; Murine MEF3.8/Bcrp1 cells	IC50 values for sulfasalazine-stimulated ATPase activity ranged from 4.4-7.3 μM. Mitoxantrone toxicity (IC50) in MEF3.8/Bcrp1 cells was significantly reduced to 2 μM (THC) and 5 μM (CBD and CBN).	(Holland et al., 2007)
	CBD	Mitoxantrone, Glyburide	Human CEM/VLB100 cells, BeWo cells, Jar cells; Human perfused placenta	Significant increase in mitoxantrone accumulation following exposure to 10 μM CBD in BeWo, Jar, and MCF7/P-gp cell lines. CBD (15 μM) increased glyburide fetal-to-maternal ratio 1.4-fold in human perfused placenta.	(Feinshtein et al., 2013)
MRP1	CBD, CBN, THC	Fluo3, Vincristine	2008/MRP1 cells	IC50 for Fluo3 accumulation: CBD = 128 μM, CBN = 145 μM, THC = 161 μM IC50 for vincristine accumulation: CBD = 38 μM, CBN = 30.9 μM, THC=107 μM	(Holland et al., 2008)
Effects of cannabinoids on efflux transporter expression
Transporter	Cannabinoid	Dose or Concentration	Experimental system(s)	Key observations	Reference
P-gp	CBD, THC	0.1, 1, 10 μM	Human CEM/VLB100 cells	P-gp expression increased by 50% after a 72-hour exposure.	(Holland et al., 2006)
	CBD, THC	10 μM	Human CEM/VLB100 cells	MDR1 mRNA expression increased by 2 and 2.5 fold, respectively, at a 4-hour, but not 8- or 48-hour, incubation.	(Arnold et al., 2012)
	CBD	15 μ	BeWo cells, Jar cells, MCF7/P-gp cells	A 72-hour exposure resulted in ~60% decrease in P-gp expression in BeWo and Jar cell lines but a ~2.5 fold increase in P-gp expression in MCF7/P-gp cell line.	(Feinshtein et al., 2013)
	THC	1 mg/kg THC ip for 14 days followed by 14 day wash-out	Mice	Increased expression of P-gp in the ventrolateral septum, nucleus accumbens core, and the paraventricular nucleus of the thalamus	(Brzozowska et al., 2017)
BCRP	THC, CBD, CBN	0.4, 4, 5 μM	WiDr human colon cells, MEF3.8/BCRP cells	No change in ABCG2 (BCRP) expression	(Holland et al., 2007)
	CBD	15 uM	BeWo cells, Jar cells	A 72-hour exposure resulted in ~2 fold increase of BCRP expression in BeWo and Jar cell lines.	(Feinshtein et al., 2013)