In Reply:—

We appreciate the letter from Dr. Grouls et al.  We agree with the authors but suggest that the issue is largely a semantic one. We should have referred to the reported permeability coefficient as the “apparent permeability coefficient” because it was calculated from the total drug concentration, not the unionized fraction. We chose to use total drug concentration for several reasons. First, total drug concentration is the clinically relevant drug quantity, and it is easy to measure accurately (as opposed to ionized fraction, which must be calculated based on pH, ionic strength, temperature, and so forth). Secondly, correcting for ionized fraction is based on the assumption that ionized solutes are impermeable across the relevant tissue. No tissue is completely impermeable to charged solutes, and we have shown that current will flow through the meninges if we place a potential across them. Admittedly, the magnitude of the current is not large, and small electrolytes (as opposed to larger charged drug molecules) may well carry the majority of the current, but we do not know that for sure. Consequently, we believe that using total drug concentration to calculate the permeability coefficient was appropriate and clinically relevant, but, to avoid confusion, we should have termed it “apparent permeability coefficient.”