Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice.
An in situ mouse brain perfusion model predictive of passive and carrier-mediated transport across the blood-brain barrier (BBB) was developed and applied to mdr1a P-glycoprotein (Pgp)-deficient mice [mdr1a(-/-)]. Cerebral flow was estimated from diazepam uptake. Physical integrity of the BBB was assessed with sucrose/inulin spaces; functional integrity was assessed with glucose uptake, which was saturable with a Km of approximately 17 mmol/L and Vmax of 310 mmol x 100 g(-1) x min(-1). Brain uptake of a Pgp substrate (colchicine) was significantly enhanced (two- to fourfold) in mdr1a(-/-) mice. These data suggest that the model is applicable to elucidating the effects of efflux transporters, including Pgp, on brain uptake.
Dagenais
C
C
Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, USA.
Rousselle
C
C
Pollack
G M
GM
Scherrmann
J M
JM
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000235:genetics*; D001921:Brain / Q000098:blood supply*; D002560:Cerebrovascular Circulation / Q000235:genetics*; D003078:Colchicine / Q000493:pharmacokinetics; D003975:Diazepam / Q000493:pharmacokinetics*; D005947:Glucose / Q000493:pharmacokinetics; D007444:Inulin / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010477:Perfusion; D013395:Sucrose / Q000493:pharmacokinetics
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D018686:Anesthetics, Intravenous; D013395:Sucrose; D007444:Inulin; C095122:multidrug resistance protein 3; D005947:Glucose; D003975:Diazepam; D003078:Colchicine