If you are doing ANY drug studies of the inner ear, you need to be aware of the content on this page
We have previously presented that the main boundaries of the body are formed by sheets of cells with tight junctions between them. The tight junctions limit drug passage between the cells. In order to pass through the cell layer the drug therefore has to pass through the cell layer. The limiting factor is the ability of the drug to pass through the lipid membranes of the cells. It has been shown that two molecular properties relevant to 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 groups). 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 tend to pass readily 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 within which molecules tend to enter the body through the gut with oral dosing. Molecules outside the white ellipse do not readily pass through the gut epithelium.
The egg plot therefore provides a valuable index of how easily a drug will pass through the membranous boundaries of the inner ear, specifically the rate they will enter perilymph following intratympanic administration and how easily they will be lost from perilymph to the vasculature.
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 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. In future publications we will detail how cochlear pharmacokinetics is correlated with the molecular properties of the drug.