caa a22 4500 445312785 CHVBK 20180317142636.0 cr unu---uuuuu 170323e20110301xx s 000 0 eng 10.1007/s11095-010-0298-0 doi (NATIONALLICENCE)springer-10.1007/s11095-010-0298-0 A New In Situ Brain Perfusion Flow Correction Method for Lipophilic Drugs Based on the pH-Dependent Crone-Renkin Equation [Elektronische Daten] [Alex Avdeef, Na Sun] ABSTRACT: Purpose: To determine the flow-corrected luminal permeability, Pc, 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, Pe, to produce Pc values. Results: It was shown by the analysis of the in situ data in the pH6.5-8.5 interval for the lipophilic bases that the average vascular flow Fpf = 0.036mL∙g−1∙s−1, centered in a "flow-limit window” (FLW) bounded by Pemin = 170 and Pemax = 776 (10−6cm∙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. Springer Science+Business Media, LLC, 2010 blood-brain barrier nationallicence brain permeability-surface area (PS) nationallicence crone-Renkin equation nationallicence PAMPA-BBB nationallicence rodent in situ brain perfusion nationallicence DRW : dynamic range window for flow-limited drugs, $$ {\hbox{DRW }} = { \log }\left( {{{\hbox{F}}_{\rm{pf}}}/{\hbox{S}}} \right){ }--{ \max }\left( {{ \log }{{\hbox{P}}_{\rm{i}}},{ \log }{{\hbox{P}}_{\rm{para}}}} \right) $$ nationallicence FLW : flow limit window: $$ {\hbox{FLW }} = { \log }\left( {{{\hbox{F}}_{\rm{pf}}}/{\hbox{S}}} \right){ }\pm { 3} $$ $$ {\hbox{SD }} = { } - {3}.{44 }\pm { }0.{33} $$ (SD = standard deviation) nationallicence Fpf : cerebrovascular flow velocity of perfusion fluid (mL·g−1·s−1 brain tissue) nationallicence Kin : unidirectional transfer constant (mL·g−1·s−1): $$ {{\hbox{K}}_{\rm{in}}} = { }\left( {{ }{{\hbox{Q}}_{\rm{br}}}/{ }{{\hbox{C}}_{\rm{pf}}}} \right){ }/{\hbox{ T}} $$, where Qbr = test compound parenchymal brain concentration (nmol·g−1 brain tissue) (corrected for the vascular volume), Cpf = perfusion fluid concentration (nmol·mL−1), T = perfusion time (s) nationallicence PABL : aqueous boundary layer permeability coefficient (cm·s−1), in vitro or PAMPA model nationallicence Papp : apparent in vitro transcellular permeability coefficient (cm·s−1) nationallicence Pc : corrected-for-flow luminal permeability coefficient (cm·s−1) depends on pH for ionizable permeants (hyperbolic function) nationallicence basis of the pH partition hypothesis nationallicence Pc S : permeability-surface area product (mL·g−1·s−1), traditionally determined from Kin using Crone-Renkin equation (CRE): $$ {{\hbox{P}}_{\rm{c}}}{\hbox{S }} = { } - { }{{\hbox{F}}_{\rm{pf}}}{ \ln }\left( {{1 }--{ }{{\hbox{K}}_{\rm{in}}}/{{\hbox{F}}_{\rm{pf}}}} \right) $$ nationallicence Pe : effective permeability coefficient (cm·s−1), not corrected for flow: $$ {{\hbox{P}}_{\rm{e}}} = { }{{\hbox{K}}_{\rm{in}}}/{\hbox{ S}} $$ depends on pH for ionizable permeants (sigmoidal function) nationallicence pH-CRE : new pH-dependent Crone-Renkin equation (CRE) flow correction method nationallicence Pi : luminal permeability coefficient (cm·s−1) of the ionized form of permeant nationallicence pKaflux : pH where 50% of the permeation is due to luminal permeability and 50% due to the effective permeability at the hydrodynamic limit nationallicence Pm : PAMPA transmembrane permeability coefficient (cm·s−1), at pH7.4, corrected for ABL nationallicence Po : intrinsic luminal permeability coefficient (cm·s−1) of the neutral form of permeant for ionizable drugs, $$ {{\hbox{P}}_{\rm{o}}} = {{\hbox{P}}_{\rm{c}}}\left( {{1}{0^{\pm ({\rm{pH }} - {\rm{ pKa}})}} + {1}} \right) $$, with ‘+' for acids, ‘-' for bases nationallicence Ppara : paracellular permeability coefficient (cm·s−1), indicating aqueous diffusion of permeant through the tight junctions formed by the blood-brain barrier nationallicence S : endothelial surface area in a gram of brain tissue (assumed to be 100cm2∙g−1) nationallicence Avdeef Alex pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut Sun Na pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/3(2011-03-01), 517-530 0724-8741 28:3<517 2011 28 11095 https://doi.org/10.1007/s11095-010-0298-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0298-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Avdeef Alex pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut NATIONALLICENCE 700 1- Sun Na pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/3(2011-03-01), 517-530 0724-8741 28:3<517 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer