A new in situ brain perfusion flow correction method for lipophilic drugs based on the pH-dependent Crone-Renkin equation

Pharm Res. 2011 Mar;28(3):517-30. doi: 10.1007/s11095-010-0298-0. Epub 2010 Nov 2.

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Flow Velocity / physiology
  • Blood-Brain Barrier / metabolism
  • Brain / blood supply*
  • Brain / metabolism*
  • Hydrogen-Ion Concentration
  • Male
  • Membrane Lipids / metabolism*
  • Pharmaceutical Preparations / metabolism*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Membrane Lipids
  • Pharmaceutical Preparations