Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• ABCB1 and ABCG2 transporters at the blood-brain barrier limit drug distribution to the brain.
• Dual substrates for ABCB1 and ABCG2 require combined transporter inhibition for increased brain uptake.

Purpose of the Study:

• To investigate the interplay between ABCB1 and ABCG2 transporters at the human blood-brain barrier.
• To assess the impact of the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A on substrate brain distribution.

Main Methods:

• Positron emission tomography (PET) was used to measure brain distribution of dual substrates ([(11)C]elacridar and [(11)C]tariquidar).
• PET scans were performed in healthy subjects with and without the ABCG2 c.421C>A SNP, under functional transporter conditions and during ABCB1 inhibition.
• A selective ABCB1 substrate, (R)-[(11)C]verapamil, was used for comparison.

Main Results:

• Dual substrates [(11)C]elacridar and [(11)C]tariquidar showed only moderate brain distribution increases during ABCB1 inhibition, unlike the ABCB1-selective substrate.
• Subjects with the c.421CA genotype exhibited significantly greater increases in [(11)C]tariquidar brain distribution during ABCB1 inhibition compared to c.421CC subjects.
• This suggests impaired cerebral ABCG2 function in individuals with the c.421CA SNP.

Conclusions:

• Evidence supports a functional interplay between ABCB1 and ABCG2 at the human blood-brain barrier.
• Simultaneous inhibition of both ABCB1 and ABCG2 is necessary to substantially increase brain distribution of dual substrates.
• The ABCG2 c.421C>A SNP may impair cerebral ABCG2 function, affecting drug delivery to the brain.