Uptake Transporters at the Blood–Brain Barrier and Their Role in Brain Drug Disposition

Abstract

Uptake drug transporters play a significant role in the pharmacokinetic of drugs within the brain, facilitating their entry into the central nervous system (CNS). Understanding brain drug disposition is always challenging, especially with respect to preclinical to clinical translation. These transporters are members of the solute carrier (SLC) superfamily, which includes organic anion transporter polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), and amino acid transporters. In this systematic review, we provide an overview of the current knowledge of uptake drug transporters in the brain and their contribution to drug disposition. Here, we also assemble currently available proteomics-based expression levels of uptake transporters in the human brain and their application in translational drug development. Proteomics data suggest that in association with efflux transporters, uptake drug transporters present at the BBB play a significant role in brain drug disposition. It is noteworthy that a significant level of species differences in uptake drug transporters activity exists, and this may contribute toward a disconnect in inter-species scaling. Taken together, uptake drug transporters at the BBB could play a significant role in pharmacokinetics (PK) and pharmacodynamics (PD). Continuous research is crucial for advancing our understanding of active uptake across the BBB.

Blood-Nanoparticle Interactions Create a Brain Delivery Superhighway for Doxorubicin

“…Additionally, the role of efflux transporters, which actively pump doxorubicin back into the bloodstream, must be considered. 18 , 35 Existing literature suggests that nanoparticles can bypass these efflux mechanisms which further increases the uptake through the cell-mediated pathway. 22 , 23 , 36 …”

“…16 Another important aspect to consider is the presence of efflux transporters such as the p-glycoprotein and ATPdependent ABC transporters, which have an impact on a wide variety of drug molecules. 17,18 One example is doxorubicin, which is affected by these multidrug resistance transporters, 19 leading to efficient elimination of the drug from the brain. PBCA nanoparticles have been demonstrated to efficiently bypass these efflux pumps in various scenarios, [19][20][21] including the delivery of substances like dalargin, loperamide, and doxorubicin to the brain in vivo.…”

Peripheral administration of sepiapterin replenishes brain tetrahydrobiopterin: a pharmacodynamic study

“…Candidates for e ux transporters involved in the BBB include various ABC transporters and SLC transporters [23,43], which also overlap with uptake transporters [22]. Biological pumping at the BBB is carried out through transcellular transport, involving the coordinated action of multiple transporters.…”

“…ENTs are almost ubiquitously distributed in parenchymal cells, both in the periphery and in the brain, and are responsible for the uptake of nucleotide precursors, nucleobases and nucleosides [20]. Probenecid-sensitive transporters, mainly containing the OAT group, are involved in the trans-epithelial clearance of metabolic wastes from various organs, including the brain [21][22][23][24]. Focusing on these transporters, we examined the pharmacokinetics of whether peripherally administered SP reaches and passes through the BBB.…”

Accurate prediction of Kp,uu,brain based on experimental measurement of Kp,brain and computed physicochemical properties of candidate compounds in CNS drug discovery

“…As of today, P-glycoprotein (P-gp) is the only transporter whose role in brain penetration is relatively well characterized. Other xenobiotic ATP-binding case (ABC) and solute carrier (SLC) transporters such as breast cancer resistance protein (BCRP), multidrug resistance-associated proteins (MRPs), organic anion transporting polypeptides (OATPs), and organic cation transporters (OCTs) are also expressed at the human BBB [ [20] , [21] , [22] , [23] ], but very little is known about their properties and roles in brain penetration. Morena [ 14 ] proposed a statistical model by using experimental K p,brain , in silico predicted f u,p and f u,b .…”