Do Multidrug Resistance‐Associated Protein‐1 and ‐2 Play Any Role in the Elimination of Estradiol‐17β‐Glucuronide and 2,4‐Dinitrophenyl‐S‐Glutathione Across the Blood–Cerebrospinal Fluid Barrier?

Abstract

The purpose of this study was to examine the role of multidrug resistance‐associated protein‐1 and ‐2 (Mrp1 and Mrp2) in the efflux transport of organic anions across the blood–cerebrospinal fluid (CSF) barrier. The CSF concentration of estradiol‐17β‐glucuronide (E217βG) and 2,4‐dinitrophenyl‐S‐glutathione (DNP‐SG) in the CSF after intracerebroventricular and intravenous injection were compared between wild‐type and Mrp1 gene knockout mice. There was no significant difference in the apparent CSF elimination rate constants of E217βG (0.158 and 0.145min.−1) and DNP‐SG (0.116 and 0.0779min.−1) between wild‐type and Mrp1 knockout mice, respectively. After intravenous administration of E217βG, its brain‐to‐serum and CSF‐to‐serum concentration ratios in Mrp1 knockout mice were not significantly different from those in the wild‐type. Results from in vivo and in vitro studies using Eisai hyperbilirubinemic rats, in which Mrp2 is hereditarily deficient, were similar to those using normal rats. Quantitative polymerase chain reaction (PCR) showed that the expression level of Mrp4 and Mrp5 was several times higher than that of Mrp1, whereas the expression levels of Mrp2, Mrp3, and Mrp6 were negligible or low. Therefore, Mrp4 and Mrp5 may contribute to the efflux transport of E217βG and DNP‐ SG from the CSF. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:99–107, 2004