Abstract
The widely expressed and poly-specific ABC transporters breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) are co-localized at the blood-brain barrier (BBB) and have shown to limit the brain distribution of several clinically used ABCB1/ABCG2 substrate drugs. It is currently not known to which extent these transporters, which are also expressed at the blood-retinal barrier (BRB), may limit drug distribution to the human eye and whether the ABCG2 reduced-function single-nucleotide polymorphism (SNP) Q141K (c.421C > A) has an impact on retinal drug distribution. Ten healthy male volunteers (five subjects with the c.421CC and c.421CA genotype, respectively) underwent two consecutive positron emission tomography (PET) scans after intravenous injection of the model ABCB1/ABCG2 substrate [11C]tariquidar. The second PET scan was performed with concurrent intravenous infusion of unlabelled tariquidar to inhibit ABCB1 in order to specifically reveal ABCG2 function.In response to ABCB1 inhibition with unlabelled tariquidar, ABCG2 c.421C > A genotype carriers showed significant increases (as compared to the baseline scan) in retinal radiotracer influx K 1 (+62 ± 57%, p = 0.043) and volume of distribution V T (+86 ± 131%, p = 0.043), but no significant changes were observed in subjects with the c.421C > C genotype. Our results provide the first evidence that ABCB1 and ABCG2 may together limit the distribution of systemically administered ABCB1/ABCG2 substrate drugs to the human retina. Functional redundancy between ABCB1 and ABCG2 appears to be compromised in carriers of the c.421C > A SNP who may therefore be more susceptible to transporter-mediated drug-drug interactions at the BRB than non-carriers.
Highlights
The transport of specific molecules across lipid membranes is an essential function of all living organisms (Liu, 2019)
We used positron emission tomography (PET) imaging to assess the functional impact of the two efflux transporters ABCB1 and ABCG2 at the blood-retinal barrier (BRB) on controlling the distribution of a model ABCB1/ABCG2 substrate ([11C]tariquidar) to the human retina
Non-clinical data indicated that tariquidar highly accumulates in the eye, which has been attributed to binding to melanin (INVESTIGATOR BROCHURE Tariquidar, 2007), which is abundantly expressed in retinal pigmental epithelial (RPE) cells (Rimpelä et al, 2018)
Summary
The transport of specific molecules across lipid membranes is an essential function of all living organisms (Liu, 2019). Many ABCG2 substrates are substrates of another ABC-transporter, P-glycoprotein (ABCB1), so that the net effect on the disposition of drugs which are dual ABCB1/ABCG2 substrates may be attributed to the combined action of both transporters These two transporters have been recognized by the International Transporter Consortium to be involved in clinically relevant transporter-mediated drug-drug interactions (DDIs) given their impact on the disposition of their substrates (International Transporter et al, 2010). The co-localization of ABCG2 and ABCB1 at several blood-tissue barriers suggests a crucial role in protecting key vulnerable and/or target tissues, e.g., the brain or the placenta, from xenobiotics and harmful metabolites. It is, difficult to predict the functional impact of ABCB1- and ABCG2-mediated efflux on tissue exposure from conventional plasma pharmacokinetic data (Wijaya et al, 2017)
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