Characterization of Dextromethorphan and Dextrorphan Uptake by a Putative Glutamic Acid Carrier and Passive Diffusion across Brain Microvessel Endothelium

Abstract

AbstractThe mechanisms of uptake and transcellular passage of dextromethorphan (DM) and its major metabolite dextrorphan (DX) across the endothelial component of the blood–brain barrier have been investigated with primary cultures of bovine brain microvessel endothelial cells (BMECs). The uptake of [14C]DM and [14C]DX by BMECs was observed to be temperature-sensitive and saturable, with approximate Km's of 0.12 and 0.29 mM and Vmax's of 9.2 and 11.0 pmol/mg/min, respectively. The BMEC uptake of [14C] DM was inhibited half-maximally by approximately 0.57 mM L-glutamic acid, 0.71 mM N-methyl-d-asparatate (NMDA), and 0.99 mM DL-threo-β-hydroxyaspartic acid. The BMEC uptake of [14C]DX was inhibited half-maximally by approximately 0.48 mM L-glutamic acid, 1.50 mM NMDA, and 0.69 mM DL-threo-β-hydroxyaspartic acid. Conversely, the bidirectional passage of DM and DX across confluent BMEC monolayers occurred at a faster rate but was neither saturable nor inhibited by high concentrations of glutamic acid, NMDA, or ...