Influence of an ABCG2 SNP on brain distribution of ABCG2 substrates

The blood-brain barrier, which is the interface between blood and the brain, protects the brain from the accumulation of potentially harmful substances, such as chemicals and drugs. The blood-brain barrier expresses the active transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), which are capable of transporting a variety of different drugs from brain back into the blood. Single nucleotide polymorphisms (SNPs) are deoxyribonucleic acid (DNA) sequence variations which can lead to altered structure or functionality of for instance proteins. ABCB1 and ABCG2 SNPs could affect the ability of these pumps to transport drugs and could thereby lead to changes in the distribution of ABCB1/ABCG2 substrate drugs (for example a drug class called tyrosine kinase inhibitors for cancer treatment) to the brain and to other organs. This could change the efficacy of such drugs or lead to unwanted side effects. Aim of this project is to assess the influence of an ABCG2 SNP (c.421C>A) on the brain and whole- body distribution of drugs by using the nuclear imaging technique positron emission tomography (PET). We will administer very small doses of two model ABCB1/ABCG2 substrates ([11C]elacridar or [11C]tariquidar) and measure their distribution to the brain and the rest of the body with a PET camera. We will perform two consecutive PET examinations, one before and one during administration of a drug which blocks ABCB1. This will permit assessing brain and whole-body distribution of [11C]elacridar and [11C]tariquidar under two different conditions, i.e. when both ABCB1 and ABCG2 are fully functional (PET scan 1) and when only ABCG2 is functional (PET scan 2). We will examine two different study groups, one group without ABCG2 SNP and one group with ABCG2 SNP. We hypothesize that carriers of the ABCG2 SNP will show a higher increase in brain distribution of [11C]elacridar and[11C]tariquidar after inhibition of ABCB1, because the functionality of ABCG2 at the blood-brain barrier is impaired as compared with subjects without the ABCG2 SNP. The results of this project will improve our understanding if an ABCG2 SNP can lead to changes in organ distribution of certain drugs, which could in turn have an impact on therapeutic response and/or side effects of drugs.

The blood-brain barrier, which is the interface between blood and the brain, protects the brain from the accumulation of potentially harmful substances, such as chemicals and drugs. The blood-brain barrier expresses the transport proteins ABCB1 and ABCG2, which are capable of transporting a variety of different drugs from brain back into the blood. Single nucleotide polymorphisms (SNPs) are deoxyribonucleic acid (DNA) sequence variations which can lead to altered structure or functionality of the encoded proteins. For ABCG2, a certain SNP called c.421C>A could affect the ability of ABCG2 to transport drugs and could thereby lead to changes in the organ distribution of certain drugs (for example a drug class called tyrosine kinase inhibitors for cancer treatment). This could change the efficacy of such drugs or lead to unwanted side effects. In this project we assessed in healthy volunteers the influence of the c.421C>A SNP on the brain distribution of the model ABCB1/ABCG2 substrate [11C]tariquidar by means of positron emission tomography (PET) imaging. We found no differences in the brain distribution of the model ABCB1/ABCG2 substrate between persons with SNP and persons without SNP. However, after pharmacological ABCB1 inhibition, persons with SNP had a markedly higher brain distribution of the model ABCB1/ABCG2 substrate than persons without SNP. This showed for the first time that the investigated SNP leads to a diminished activity of ABCG2 at the human blood-brain barrier and that SNP carriers may be potentially more vulnerable to drug-drug interactions at the blood-brain barrier.