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-me diated transport across the blood-brain barrier (BBB) was developed and app lied to mdr1a P-glycoprotein (Pgp)-deficient mice [mdr1a(-/-)]. Cerebral fl ow was estimated from diazepam uptake. Physical integrity of the BBB was as sessed with sucrose/inulin spaces; functional integrity was assessed with g lucose uptake, which was: saturable with a K-m of similar to 17 mmol/L and V-max of 310 mmol . 100 g(-1). min(-1). Brain uptake of a Pgp substrate (co lchicine) 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.