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

✍ Scribed by Donna S. Cox; Kenneth R. Scott; Huanling Gao; Sangeeta Raje; Natalie D. Eddington

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 207 KB
• Volume: 90
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.1104

✦ Synopsis

Previous in vitro studies evaluating the permeability of enaminones suggested that their blood±brain barrier (BBB) transport might be in¯uenced by the presence of an ef¯ux mechanism. Therefore, transport mechanisms responsible for these anticonvulsants across the BBB were examined. The transport of enaminones (1Â10 À4 M) were evaluated over 120 min with verapamil (50 mM) and probenecid (100 mM) using bovine brain microvessel endothelial cells (BBMECs) to assess the role of multidrug resistant (MDR) transport proteins [i.e., P-glycoprotein (Pgp) and MDR protein 1 (MRP1)] on ef¯ux, respectively. Uptake studies in the presence and absence of rhodamine 123 (R123; 3.2 and 5.0 mM) were also performed in a Pgp overexpressing cell line, MCF-7/Adr. Select enaminone esters (12.5 mg/kg) were administered intravenously to mdr 1 a/b (/), mdr 1 a/b (À/À) knockout and probenecid pretreated mice (20 AE 5g). Enaminones and R123 were assayed with validated ultraviolet and ¯uorescence high-performance liquid chromatography methods, respectively. Verapamil and probenecid signi®cantly (pb0.05) inhibited the transport of select enaminone esters across BBMECs. Two enaminones caused a statistically signi®cant increase in the uptake of R123 in MCF-7/Adr cells. Concentrations of select enaminones in mdr 1 a/b (À/À) mice brains were signi®cantly higher (p`0.05) compared with those in mdr 1 a/b (/) mice brains; however, no differences were observed in probenecid pretreated animals. Taken together, these results strongly suggest that Pgp may in¯uence enaminone transport at the BBB and hence affect epilepsy treatment with these agents.