Cannabis L. (Cannabis sativa)
Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). CSV JSON

Drug interaction with P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) may influence its tissue disposition including blood-brain barrier transport and result in potent drug-drug interactions. The limited data obtained using in-vitro models indicate that methadone, buprenorphine, and cannabinoids may interact with human P-gp; but almost nothing is known about drugs of abuse and BCRP. We used in vitro P-gp and BCRP inhibition flow cytometric assays with hMDR1- and hBCRP-transfected HEK293 cells to test 14 compounds or metabolites frequently involved in addiction, including buprenorphine, norbuprenorphine, methadone, ibogaine, cocaine, cocaethylene, amphetamine, N-methyl-3,4-methylenedioxyamphetamine, 3,4-methylenedioxyamphetamine, nicotine, ketamine, Delta9-tetrahydrocannabinol (THC), naloxone, and morphine. Drugs that in vitro inhibited P-gp or BCRP were tested in hMDR1- and hBCRP-MDCKII bidirectional transport studies. Human P-gp was significantly inhibited in a concentration-dependent manner by norbuprenorphine>buprenorphine>methadone>ibogaine and THC. Similarly, BCRP was inhibited by buprenorphine>norbuprenorphine>ibogaine and THC. None of the other tested compounds inhibited either transporter, even at high concentration (100 microm). Norbuprenorphine (transport efflux ratio approoximately 11) and methadone (transport efflux ratio approoximately 1.9) transport was P-gp-mediated; however, with no significant stereo-selectivity regarding methadone enantiomers. BCRP did not transport any of the tested compounds. However, the clinical significance of the interaction of norbuprenorphine with P-gp remains to be evaluated.

1 . Rh-123-THC (id=NPDI-S4_OQA)

In Vitro Transporter Inhibition Experiment

Inhibition was detected.  Cutoff used — "The mean accumulation index had to be significantly > 1 (p < 0.05) to assess transporter inhibition potency by flow cytometry (n = 3 minimum)."

  • P-gp (ABCB1)

Transfected / siRNA knock-out / injected cells HEK293 transfected cells

Results

Fig 2b
PSC833 5 μM was used as a positive control

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Assay Conditions

1 hr

37ºC

1.5 μM

50 μM

Sigma-Aldrich

2 . Calcein-AM-THC (id=NPDI-LCPweA)

In Vitro Transporter Inhibition Experiment

Inhibition was detected.  Cutoff used — "The mean accumulation index had to be significantly > 1 (p<0.05) to assess transporter inhibition potency by flow cyotmetry (n = 3 minimum)"

calcein-AM

  • P-gp (ABCB1)

Transfected / siRNA knock-out / injected cells HEK293 transfected cells

Results

Fig 2a.
PSC833 5 μM was used as a positive control

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Assay Conditions

1 hr

37ºC

1.5 μM

50 μM

Sigma-Aldrich