A Proof-of-Concept Study to Inhibit ABCG2- and ABCB1-Mediated Efflux Transport at the Human Blood–Brain Barrier

Abstract

The adenosine triphosphate-binding cassette transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are 2 efflux transporters at the blood-brain barrier (BBB) that effectively restrict brain distribution of dual ABCB1/ABCG2 substrate drugs, such as tyrosine kinase inhibitors. Pharmacologic inhibition of ABCB1/ABCG2 may improve the efficacy of dual-substrate drugs for treatment of brain tumors, but no marketed ABCB1/ABCG2 inhibitors are currently available. In the present study, we examined the potential of supratherapeutic-dose oral erlotinib to inhibit ABCB1/ABCG2 activity at the human BBB. Methods: Healthy men underwent 2 consecutive PET scans with 11 C-erlotinib: a baseline scan and a second scan either with concurrent intravenous infusion of the ABCB1 inhibitor tariquidar (3.75 mg/min, n 5 5) or after oral intake of single ascending doses of erlotinib (300 mg, n 5 7; 650 mg, n 5 8; or 1,000 mg, n 5 2). Results: Although tariquidar administration had no effect on 11 C-erlotinib brain distribution, oral erlotinib led, at the 650-mg dose, to significant increases in volume of distribution (23% ± 13%, P 5 0.008), influx rate constant of radioactivity from plasma into brain (58% ± 26%, P 5 0.008), and area under the brain time-activity curve (78% ± 17%, P 5 0.008), presumably because of combined partial saturation of ABCG2 and ABCB1 activity. Inclusion of further subjects into the 1,000-mg dose group was precluded by adverse skin events (rash). Conclusion: Supratherapeutic-dose erlotinib may be used to enhance brain delivery of ABCB1/ABCG2 substrate anticancer drugs, but its clinical applicability for continuous ABCB1/ABCG2 inhibition at the BBB may be limited by safety concerns. http://jnm.snmjournals.org/content/60/4/486 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

“…Radiolabeled substrates or inhibitors of the ABC transporters can be used to study their function, but one of the difficulties encountered is the need for specific probes due to overlapping substrate and inhibitor affinities (Section 3.2). [ 11 C]erlotinib [249][250][251] [263][264][265] have been used to specifically visualize P-gp function because they are not transported by BCRP. To date, there is no specific PET tracer for BCRP, as the compounds developed as specific molecules, such as [ 67 Ga]Galmydar, showed no significant difference between BCRP knockout and wild-type mice or rats [266][267][268], and it would not be ideal to substrate the specific activity of P-gp from that of a P-gp/BCRP common substrate, as their function is synergic and not additive [53,98].…”

“…Among other applications, TEP has been used to asses P-gp and BCRP function and inhibition in mouse [238,253,270], rat [261,271], primate [250,264] and human [251,254] models; and it could be used for precision medicine through the evaluation of individual variability in response to CNS drugs [272]. In addition, diverse strategies have been developed to study for instance drug-drug interactions of unlabeled molecules in combination with already available tracers [246].…”

“…PET was recently employed to validate the permeability and transporter function of a human iPSCs BBB model [172] and the evaluation of ABC transporter-humanized mice models [238,270]. Importantly, it has been used to evaluate drug delivery strategies, such as inhibition [250,251] or focused ultrasounds [273] (see Section 6.5 for details).…”

Pharmacokinetic Imaging with Radiolabeled Molecularly Targeted Anticancer Drugs

“…We would like to thank van de Stadt and colleagues for their positive and encouraging comments regarding our study recently published in The Journal of Nuclear Medicine (1). The central nervous system (CNS) is a pharmacologic sanctuary site in tumor treatment, due to the expression of ABCB1 and ABCG2 at the blood-brain barrier (BBB), which effectively restricts the brain distribution of most currently known anticancer agents.…”

“…The central nervous system (CNS) is a pharmacologic sanctuary site in tumor treatment, due to the expression of ABCB1 and ABCG2 at the blood-brain barrier (BBB), which effectively restricts the brain distribution of most currently known anticancer agents. In our work, we have provided one possible mechanistic explanation for the improved efficacy of supratherapeutic dose erlotinib in the treatment of non-small cell lung cancer (NSCLC) CNS metastases, which is partial saturation of ABCG2-and ABCB1-mediated efflux transport of erlotinib at the BBB (1). This nonlinearity in erlotinib brain distribution may be exploited to achieve higher brain exposure of erlotinib itself or of concomitantly administered anticancer drugs, which are subject to efflux transport by ABCG2 and ABCB1 at the BBB.…”