The Role of Size and Charge for Blood–Brain Barrier Permeation of Drugs and Fatty Acids

Abstract

The lipid bilayer is the diffusion barrier of biological membranes. Highly protective membranes such as the bloodbrain barrier (BBB) are reinforced by ABC transporters such as P-glycoprotein (MDR1, ABCB1) and multidrug resistance associated proteins (MRPs, ABCCs). The transporters bind their substrates in the cytosolic lipid bilayer leaflet before they reach the cytosol and flip them to the outer leaflet. The large majority of drugs targeted to the central nervous system (CNS) are intrinsic substrates of these transporters. Whether an intrinsic substrate can cross the BBB depends on whether passive influx is higher than active efflux. In this paper, we show that passive influx can be estimated quantitatively on the basis of Stokesian diffusion, taking into account the ionization constant and the cross-sectional area of the molecule in its membrane bond conformation, as well as the lateral packing density of the membrane. Active efflux by ABC transporters was measured. The calculated net flux is in excellent agreement with experimental results. The approach is exemplified with several drugs and fatty acid analogs. It shows that compounds with small cross-sectional areas (A D <70 Å 2 ) and/ or intermediate or low charge exhibit higher passive influx than efflux and, therefore, cross the BBB despite being intrinsic substrates. Large (A D >70 Å 2 ) or highly charged compounds show higher efflux than influx. They cannot cross the BBB and are, thus, apparent substrates for ABC transporters. The strict size and charge limitation for BBB permeation results from the synergistic interaction between passive influx and active efflux.

The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP

“…Inhibition of the in vitro transepithelial transport of both compounds at concentrations of TCBZ metabolites below 15 M could not be excluded. Inhibition in transepithelial transport experiments can be expected as long as the concentration of the drug is higher than the concentration at maximum activity in an ATPase assay (for all three compounds, in the ABCG2 ATPase activity profiles, the maximum activity was reported at around 1 M) (27). The similar inhibitory power of TCBZSO and TCBZSO 2 that was observed in transport assays is due to the similar concentration of half-maximum inhibition in ATPase assays (Fig.…”

Identification and Characterization of Mefloquine Efficacy against JC Virus In Vitro

“…1D) anti-JCV activity in vitro at the doses achievable in the plasma of treated patients (10 M); brain biodistribution data do not appear to be available for this drug. Data addressing the ability of alpha interferon to cross the BBB are also lacking, but on the basis of the size of the interferon molecule and its short half-life in blood, one may predict that it would not accumulate in the brain in significant amounts (53). Because JCV infects and replicates in cells throughout the entire white matter of the brain, an effective drug candidate for the treatment of PML must be able to cross the BBB and accumulate throughout the entire brain parenchyma at a dose sufficient to suppress JCV proliferation.…”

Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier

“…Our data suggests that the drugs we used are either not transported by P-glycoprotein or they inhibit its activity. Alternatively, these APs may possess passive membrane permeability so high such that their rate of influx is larger than, and overwhelms that, of the Pglycoprotein efflux pathway; a scenario already demonstrated for CPZ in 20 BBB models (Seelig, 2007). Although these APs at ~30µM can stimulate the ATPase activity of P-glycoprotein and are perhaps substrates for transportation (Boulton et al, 2002), the observation that at similar concentrations they actually inhibit the ability of this protein to extrude the amphiphilic molecule, RH123 from cells (Wang et al, 2006) at excessively high concentrations of APs subsequent damage to the BBB would make it leaky, not just to blood solutes and components with ensuing extravasation (Pardridge et al, 1973;Ben-Schachar et al, 1994), were purchased from Sigma-Aldrich (Poole, UK) unless stated otherwise.…”