Current Pharmaceutical Design - Volume 20, Issue 10, 2014

The blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSF) barriers are critical determinants of CNS homeostasis. Additionally, the BBB and BCSF barriers are formidable obstacles to effective CNS drug delivery. These brain barrier sites express putative influx and efflux transporters that precisely control permeation of circulating solutes including drugs. The study of transporters has enabled a shift away from “brute force Read More

Since the discovery of P-glycoprotein (P-gp) in brain microvessels composing the human blood-brain barrier (BBB), ATPbinding cassette (ABC) transporters have been recognized as bottlenecks in the development and delivery of neuropharmaceuticals. ABC transporters are expressed predominately at the plasma luminal membrane of brain capillary endothelial cells. These ABC transporters are responsible for the efflu Read More

At the blood-brain barrier, ATP-binding cassette (ABC) transporters, such as, P-glycoprotein (MDR1, ABCB1) and breast cancer related protein (BCRP, ABCG2) limit CNS uptake of foreign chemicals. Thus, they are neuroprotective, but they also distinguish poorly between neurotoxicants and therapeutic drugs. So they are major obstacles to CNS pharmacotherapy. The present review is focused on new findings in animal mode Read More

A major function of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCSFB) is to exert selective control over the flux of organic cations and anions into and out of the CNS compartment. These barriers are dynamic tissues that accomplish this task by expressing dozens of transporter proteins representing numerous transporter families. One such family, belonging to the Solute Carrier (SLC) superfamily, is t Read More

Monocarboxylate transporters (MCTs) are known to mediate the transport of short chain monocarboxylates such as lactate, pyruvate and butyrate. Currently, fourteen members of this transporter family have been identified by sequence homology, of which only the first four members (MCT1- MCT4) have been shown to mediate the proton-linked transport of monocarboxylates. Another transporter family involved in the transpo Read More

The delivery of many drugs to the central nervous system (CNS) is limited due to the restrictive nature of the blood-brain barrier (BBB). The reduced paracellular diffusion and the presence of various drug efflux transporters in the brain microvessel endothelial cells forming the BBB make effective treatment of brain tumors with chemotherapeutic agents particularly problematic. While Pglycoprotein (P-gp) plays an importa Read More

Cerebral ischemia is one of the major causes of disability worldwide. In cerebral ischemic stroke, occlusion of a major cerebral artery by an embolus or local thrombosis can result in transient or permanent reduction of cerebral blood flow to a portion of the brain, resulting in deprivation of glucose and oxygen. Since the brain relies on a continuous supply of nutrients and ions via mostly carrier mediated processes across Read More

Molecular transporters that are expressed in brain, especially at the blood-brain barrier (BBB), are increasingly recognized as possible therapeutic targets in the treatment of neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Some ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (ABCB1), MRP1 (ABCC1) and BCRP (ABCG2), have been implicated in the clearance of neurotoxi Read More

Unfortunately, antiepileptic drug therapy fails to control seizure activity in a relevant percentage of epilepsy patients. Epidemiological data as well as findings in human epileptic tissue and in rodent models indicate that drug resistance is a multi-factorial phenomenon with various factors contributing to therapeutic failure. Enhanced efflux transport of antiepileptic drugs as a consequence of seizure-associated up-regulatio Read More

Membrane-associated drug transporters are important determinants of antiretroviral drug disposition in the central nervous system during HIV-1 infection. A number of influx and efflux transport proteins expressed at the blood-brain barrier, blood-cerebrospinal fluid barrier and in brain parenchyma cellular compartments (i.e., astrocytes, microglia) have been implicated in the traffic of many antiretroviral drugs into and Read More

The blood-brain barrier (BBB) represents a large obstacle for the treatment of central nervous system diseases. Targeting endogenous nutrient transporters that transcytose the BBB is one promising approach to selectively and noninvasively deliver a drug payload to the brain. The main limitations of the currently employed transcytosing receptors are their ubiquitous expression in the peripheral vasculature and the inher Read More

Over the recent years there has been a greater appreciation in the important roles drug transporters play in drug-drug interactions (DDI), safety and effectiveness of drugs. Notable consequence of this recognition includes the white paper published by the International Transporter Consortium (ITC) and the guidance documents drafted by regulatory agencies for investigating transporter-mediated DDIs during drug development. Read More