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

• Published in: Journal of Nuclear Medicine Vol. 60; no. 4; pp. 486 - 491
• Main Authors: Bauer, Martin, Karch, Rudolf, Wulkersdorfer, Beatrix, Philippe, Cécile, Nics, Lukas, Klebermass, Eva-Maria, Weber, Maria, Poschner, Stefan, Haslacher, Helmuth, Jäger, Walter, Tournier, Nicolas, Wadsak, Wolfgang, Hacker, Marcus, Zeitlinger, Markus, Langer, Oliver
• Format: Journal Article
• Language: English
• Published: United States Society of Nuclear Medicine 01-04-2019
• Subjects: Adenosine triphosphate; Administration, Oral; Adult; Antineoplastic drugs; Antitumor agents; ATP; ATP Binding Cassette Transporter, Subfamily G, Member 2 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily G, Member 2 - metabolism; Biological Transport - drug effects; Blood; Blood-brain barrier; Blood-Brain Barrier - diagnostic imaging; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain; Brain tumors; Breast cancer; Dose-Response Relationship, Drug; Drug delivery systems; Drug dosages; Drugs; Efflux; Erlotinib Hydrochloride - administration & dosage; Erlotinib Hydrochloride - pharmacokinetics; Erlotinib Hydrochloride - pharmacology; Glycoproteins; Humans; Inhibitors; Intravenous administration; Intravenous infusion; Kinases; Male; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; P-Glycoprotein; Pharmacology; Positron emission; Positron emission tomography; Protein-tyrosine kinase; Radioactivity; Skin; Substrate inhibition; Substrates; Tissue Distribution; Tomography; Tyrosine; P-glycoprotein; blood–brain barrier; 11C-erlotinib; breast cancer resistance protein; PET
• ISSN: 0161-5505; 1535-5667; 2159-662X
• DOI: 10.2967/jnumed.118.216432

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.
: Healthy men underwent 2 consecutive PET scans with
C-erlotinib: a baseline scan and a second scan either with concurrent intravenous infusion of the ABCB1 inhibitor tariquidar (3.75 mg/min,
= 5) or after oral intake of single ascending doses of erlotinib (300 mg,
= 7; 650 mg,
= 8; or 1,000 mg,
= 2).
: Although tariquidar administration had no effect on
C-erlotinib brain distribution, oral erlotinib led, at the 650-mg dose, to significant increases in volume of distribution (23% ± 13%,
= 0.008), influx rate constant of radioactivity from plasma into brain (58% ± 26%,
= 0.008), and area under the brain time-activity curve (78% ± 17%,
= 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).
: 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.