A New In Situ Brain Perfusion Flow Correction Method for Lipophilic Drugs Based on the pH-Dependent Crone-Renkin Equation

Abstract

To determine the flow-corrected luminal permeability, P(c), of lipophilic drugs measured by the in situ brain perfusion method under circumstances where the traditional Crone-Renkin equation (CRE) method, using diazepam as a flow marker, often fails. The pH-dependent rate of brain penetration of five lipophilic drugs (amitriptyline, atomoxetine, imipramine, indomethacin, maprotiline, sertraline), as well as of atenolol and antipyrine, were measured in Sprague-Dawley rats. A new pH-dependent CRE was derived and applied to remove the hydrodynamic component of effective permeability, P(e), to produce P(c) values. It was shown by the analysis of the in situ data in the pH 6.5-8.5 interval for the lipophilic bases that the average vascular flow F(pf) = 0.036 mL∙g(-1)∙s(-1), centered in a "flow-limit window" (FLW) bounded by P (e) (min) = 170 and P (e) (max) = 776 (10(-6) cm∙s(-1) units). It was shown that the traditional CRE is expected not to work for half of the molecules in the FLW and is expected to underestimate (up to 64-fold) the other half of the molecules. The new pH-CRE flow correction method applied to lipophilic ionizable drugs, based on the pH partition hypothesis, can overcome the limitations of the traditional CRE.