The information on this page is essential reading for anyone involved in local drug delivery to the inner ear.
The main internal barriers of the body are formed by sheets of cells with "tight junctions" between them. The tight junctions limit the passage of drugs between the cells. In order to get through the cell layer the drug therefore has to pass through the cells. The main limiting factor controlling entry is how easily the drug passes through the lipid membranes of the cells. It has now been shown that two molecular properties controlling the passage of drugs across membranous biological barriers are:
1) WLOGP This is a measure of the partition coefficent of the molecule between aqueous and lipid phases. Previously this has been measured experimentally by quantifying the distribution of the molecule between octanol and water. It can now be calculated for any molecule.
2) TPSA This is a measure of the surface area of the molecule covered by polar groups (such as OH- and NH+). Non polar regions of the molecule (carbon rings and chains) do not contribute to this measure. TPSA can also be calculated for any molecule.
Both of these properties can be calculated by the SwissADME website, one of the truly best web sites on the planet. Below we will give details of how to do this for any drug. The website calculates both WLOGP and TPSA and presents it on an "egg plot", as shown below.
In this case we have calculated values for the free-alcohol form of dexamethasone, the commonly-used pro-drug, dexamethasone-phosphate and for gentamicin. Molecules at the upper left of the plot (high WLOGP (lipophilic) and low TPSA (few polar groups)) tend to be insoluble in water but pass through lipid membranes with ease. In contrast, molecules at the lower right (low WLOGP (hydrophilic) and high TPSA (a lot of polar groups)) tend to be water-soluble but not easily pass through lipid membranes. On the basis of such an analysis we expect dexamethasone to pass through boundaries more readily than dexamethasone-phosphate and for gentamicin to be retained in perilymph well. Experimental pharmacokinetic studies of the ear have confirmed that this is correct.
In the plot above, the yellow ellipse ("egg yolk") is a statistical boundary. Molecules within the "yolk area" tend to pass from the vasculature to the brain, while molecules outside the yolk do not readily enter the brain. Similar the white ellipse ("egg white") defines the boundary inside which molecules tend to enter the body through the gut with oral dosing. Molecules outside the white ellipse are not readily taken up through the gut epithelium.
The egg plot therefore provides a valuable index of how easily a drug will pass through membranous boundaries, including those of the inner ear. Specifically they control:
1) How easily drugs pass across the Round Window Membrane (i.e. how easily they get from the middle ear into perilymph).
2) How readily the drugs leak from perilymph to the vasculature, through the endothelial cells of the blood capillaries. The rate of elimination has a huge influence on how far drugs become distributed along the length of the cochlear spiral.
In order to calculate how your molecule lies on the egg plot, you can either 1) define your molecule graphically on the SwissADME website, or 2) you can find your drug molecule on PubChem. If the drug is found by the PubChem search, scroll down though the available information and locate the "Canonical Smiles" section.
The SMILES is a string of characters that define the molecule. Copy the string to your clipboard and paste it into the "Smiles" box on the SwissADME website. If you wish, add a space and give the name of the molecule and the calculations will name the molecule. The website will then calculate the molecular properties of the substance and produce an egg-plot if the properties fall within the range of the plot. The WlogP and TPSA values can be entered into the appropriate columns of the "Molecules" page, which the model uses to calculate kinetic parameters.