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

Several drugs used in addiction treatment and substances of abuse inhibit the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro, which could alter their distribution in the body, including across the blood-brain barrier. Norbuprenorphine, buprenorphine, methadone, ibogaine, and THC inhibited P-gp in a concentration-dependent manner, with norbuprenorphine being the strongest. Buprenorphine, norbuprenorphine, ibogaine, and THC inhibited BCRP. Cocaine, amphetamine, nicotine, morphine, and others did not inhibit either transporter. Norbuprenorphine and methadone were transported by P-gp, but no tested compounds were transported by BCRP. The clinical relevance of norbuprenorphine's interaction with P-gp remains unclear.

Study at a glance

Abstract

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.