RT Journal Article
SR Electronic
T1 Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using <em>mdr1a</em>-Deficient Rats and Mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 461
OP 466
DO 10.1124/dmd.111.043083
VO 40
IS 3
A1 Bundgaard, Christoffer
A1 Jensen, Christian Jes Nyberg
A1 Garmer, Mats
YR 2012
UL http://dmd.aspetjournals.org/content/40/3/461.abstract
AB The experiments described herein compared the extent of in vivo P-glycoprotein (P-gp)-mediated brain efflux between rats and mice for a set of known central nervous system compounds. With use of newly introduced genetically modified mdr1a-deficient rats and their gene-competent counterparts, the brain to plasma distribution was assessed and compared with the distribution pattern in mdr1a-deficient and wild-type mice. Four compounds (aripiprazole, citalopram, risperidone, and venlafaxine) were administered using a continuous subcutaneous osmotic minipump infusion paradigm. Steady-state brain and plasma concentrations of the compounds, including selected metabolites (9-hydroxyrisperidone, O-desmethyl-venlafaxine and N-desmethyl-venlafaxine) were measured in mdr1a-deficient rats and mice and their wild-type counterparts along with their free fractions to determine total and unbound brain to plasma distribution between genotypes within and between species. The results revealed qualitative as well as quantitative similarities between P-gp functionality in vivo at the blood-brain barrier level in rats and mice. All compounds tested were shown to have a significantly higher brain to plasma distribution in both mdr1a-deficient rats and mice compared with that in their wild-type counterparts. Moreover, the relative enhancement in extent of brain penetration between mdr1a-deficient and wild-type rats could be directly correlated to the enhancement ratios obtained in mice. From the unbound brain to unbound plasma distributions, the impact of P-gp on the overall brain penetration capabilities showed minor differences between rats and mice for the compounds tested. In conclusion, a comparable functional role of P-gp between rats and mice with respect to brain efflux mediated by this transporter is suggested.