Influence of multidrug resistance (MDR) proteins at the blood-brain barrier on the transport and brain distribution of enaminone anticonvulsants

Previous in vitro studies evaluating the permeability of enaminones suggest ed that their blood-brain barrier (BBB) transport might be influenced by th e presence of an efflux mechanism. Therefore, transport mechanisms responsi ble for these anticonvulsants across the BBB were examined. The transport o f enaminones (1 x 10(-4) M) were evaluated over 120 min with verapamil (50 muM) and probenecid (100 muM) using bovine brain microvessel endothelial ce lls (BBMECs) to assess the role of multidrug resistant (MDR) transport prot eins [i.e., P-glycoprotein (Pgp) and MDR protein 1 (MRP1)] on efflux, respe ctively. Uptake studies in the presence and absence of rhodamine 123 (R123; 3.2 and 5.0 muM) were also performed in a Pgp overexpressing cell line, MC F-7/Adr. Select enaminone esters (12.5 mg/kg) were administered intravenous ly to mdr 1 a/b (+/+), mdr 1 a/b (-/-) knockout and probenecid pretreated m ice (20 +/- 5g). Enaminones and R123 were assayed with validated ultraviole t and fluorescence high-performance liquid chromatography methods, respecti vely. Verapamil and probenecid significantly (p > 0.05) inhibited the trans port of select enaminone esters across BBMECs. Two enaminones caused a stat istically significant increase in the uptake of R123 in MCF-7/Adr cells. Co ncentrations of select enaminones in mdr 1 a/b mice brains were significant ly higher (p > 0.05) compared with those in mdr 1 a/b mice brains; however, no differences were observed in probenecid pretreated animals. Taken toget her, these results strongly suggest that Pgp may influence enaminone transp ort at the BBB and hence affect epilepsy treatment with these agents. (C) 2 001 Wiley-Liss, Inc. and the American Pharmaceutical Association.