ATP-binding cassette transporter inhibitor potency and substrate drug affinity are critical determinants of successful drug delivery enhancement to the brain.

Publisher: Biomed Central Country of Publication: England NLM ID: 101553157 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-8118 (Electronic) Linking ISSN: 20458118 NLM ISO Abbreviation: Fluids Barriers CNS Subsets: MEDLINE

Original Publication: London : Biomed Central

Mice, Knockout* ; Tetrahydroisoquinolines*/pharmacology ; Tetrahydroisoquinolines*/administration & dosage ; ATP Binding Cassette Transporter, Subfamily G, Member 2*/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2*/antagonists & inhibitors ; Brain*/metabolism ; Brain*/drug effects ; Acridines*/pharmacology ; Acridines*/administration & dosage ; Blood-Brain Barrier*/metabolism ; Blood-Brain Barrier*/drug effects; Animals ; Mice ; Quinolines/pharmacology ; Quinolines/pharmacokinetics ; Quinolines/administration & dosage ; Drug Delivery Systems/methods ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily B/genetics ; Male ; Mice, Inbred C57BL

Background: Pharmacotherapy for brain diseases is severely compromised by the blood-brain barrier (BBB). ABCB1 and ABCG2 are drug transporters that restrict drug entry into the brain and their inhibition can be used as a strategy to boost drug delivery and pharmacotherapy for brain diseases.
Methods: We employed elacridar and tariquidar in mice to explore the conditions for effective inhibition at the BBB. Abcg2;Abcb1a/b knockout (KO), Abcb1a/b KO, Abcg2 KO and wild-type (WT) mice received a 3 h i.p. infusion of a cocktail of 8 typical substrate drugs in combination with elacridar or tariquidar at a range of doses. Abcg2;Abcb1a/b KO mice were used as the reference for complete inhibition, while single KO mice were used to assess the potency to inhibit the remaining transporter. Brain and plasma drug levels were measured by LC-MS/MS.
Results: Complete inhibition of ABCB1 at the BBB is achieved when the elacridar plasma level reaches 1200 nM, whereas tariquidar requires at least 4000 nM. Inhibition of ABCG2 is more difficult. Elacridar inhibits ABCG2-mediated efflux of weak but not strong ABCG2 substrates. Strikingly, tariquidar does not enhance the brain uptake of any ABCG2-subtrate drug. Similarly, elacridar, but not tariquidar, was able to inhibit its own brain efflux in ABCG2-proficient mice. The plasma protein binding of elacridar and tariquidar was very high but similar in mouse and human plasma, facilitating the translation of mouse data to humans.
Conclusions: This work shows that elacridar is an effective pharmacokinetic-enhancer for the brain delivery of ABCB1 and weaker ABCG2 substrate drugs when a plasma concentration of 1200 nM is exceeded.
(© 2024. The Author(s).)

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Keywords: ABCB1; ABCG2; Blood-brain barrier; Drug delivery; Elacridar; Mice; Protein binding; Tariquidar

N488540F94 (Elacridar)
0 (Tetrahydroisoquinolines)
0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
0 (Acridines)
J58862DTVD (tariquidar)
0 (Abcg2 protein, mouse)
0 (Quinolines)
0 (ATP Binding Cassette Transporter, Subfamily B)

Date Created: 20240805 Date Completed: 20240806 Latest Revision: 20240808

20240808

PMC11301932

10.1186/s12987-024-00562-4

39103921