Permeability of the Blood–Brain Barrier: Molecular Mechanism of Transport of Drugs and Physiologically Important Compounds

Abstract

A new molecular model for the permeability of drugs and other physiologically important compounds to cross the blood-brain barrier has been developed. Permeability (log PS) is dependant on desolvation, lipophilicity, molecular volume and dipole moment. Previous models for BBB permeability have not considered desolvation and dipole moment as critical factors. The model applies to passive diffusion processes, and some facilitated diffusion processes. Passive permeability models may not apply to active transport processes, where complex membrane protein binding processes (e.g. stereoselectivity) are involved. Model phosphatidylcholine lipid bilayer membranes have been used to evaluate how charged or polar neutral compounds can interact through their molecular dipoles with the cell membrane to induce electromechanical changes in the cell membrane which facilitate permeation. The free energy of solvation in n-octanol has been shown to be a good measure of membrane lipophilicity by calculating the solvation free energy of a model PC lipid membrane in a series of closely related alcohols. The passive diffusion model for alcohols correlates with the known modulation of membrane bilayers which showed a size-dependent "cut-off" point in potency. For most drugs and related molecules, the neutral species are the permeating species.

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

“…4 Even drugs that do not interact with cell membranes must pass through this barrier in order to reach their intracellular targets. 5,6 As a result, a fundamental knowledge of the passive diffusion of small peptides is essential towards understanding all of these processes on both a theoretical and practical level. Rather than taking a macromolecular approach, we focus on the basic building blocks of these larger constructs-amino acids.…”

The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery

“…There is strong independent evidence from the literature that ΔG desolvation , ΔG lipophilicity , the dipole moment and molecular volume are good inherent indicators of the transport or binding ability of drugs. [33][34][35][36][37][38][39][40] [Fong 2015-16]. is calculated from the solvation energy in n-octane.…”

“…34 [Fong 2015] Eqs 2a and 2b can be directly compared to assess the difference in diffusion for the test set of TPZ derivatives between the collagen coated Teflon support membrane (which has a porosity of 11%, and pore size of 0.4 μm) and the MCL coated membrane. The D MCL equation shows a negative increased dependency on the desolvation, lipophilicity and dipole moment compared to the D S equation 2 but no change in dependency on molecular volume.…”

“…The influence of molecular volume is much larger than those exerted by lipophilicity, desolvation and dipole moment, suggesting that the primary mechanism of diffusion in this system is driven by desolvation of the TPZ analogues prior to entering the cellular membrane, followed by a polar or electrostatic interaction between the desolvated analogue and the outer hydrophilic head groups of the membrane phospholipid bilayer, followed by the ease that more lipophilic analogues can then permeate into the inner hydrophobic membrane bilayer, where molecular volume also has a large influence. 34 [Fong 2015] Eq 3 can be compared with the equation derived by Pruijn 2008 23 where log D MCL = a + b logMW + c / 1+ exp {(log P 7.4 -x + y.HD + z.HA)/w} where MW is the molecular weight, log P 7.4 is the octanol-water partition coefficient at pH 7.4, HD is the number of hydrogen bond donors, HA is the number of hydrogen bond acceptors, a is a constant, and b, c, x, y, z and w are statistically fitted coefficients. This equation is highly statistically significant, but does have 6 fitted coefficients.…”

“…We have previously shown that desolvation is a significant factor in cell membrane permeation and facilitated diffusion (as well as active transport processes). 33,35,25,38 [Fong 2015 Eq 4 and 5 show the diffusion behaviour if the TPZ species were anion radicals. This hypothetical situation (which assumes that diffusion of radical species is similar with that of neutral species but it is the charge on the radical anion which ultimately determines diffusion of these species) could exist under certain clinical situation where for example where ionizing radiation was being used, with TPZ acting as a radiosensitizer 47 [Seiwert 2006] such as might occur with when co-administered with cisplatin, or in hypoxic regions of a solid tumour, or where metabolic reduction had occurred.…”