Previous determinations of the transport and metabolic parameters of quinolinic acid in brain tissue by multiple isotope microdialysis indicated that this compound is actively transported out of the brain. To ascertain whether the active efflux system involved could be identified with the general acid transporter present at the level of the brain microvasculature, experiments were initiated in which efflux rates of quinolinic acid (QUIN) were monitored in the presence and absence of probenecid. Gerbils were administered probenecid systemically by intraperitonal injection at 400 mg/kg or intrastriatally by a microdialysis probe infused with a 10mM solution of probenecid in PBS buffer. Eluents were collected from microdialysis probes placed in the striatum, and analyzed for QUIN by electron capture mass spectrometry and homovanillic acid (HVA) by reverse phase HPLC. Time dependent changes from control values of each compound were computed for each route of administration of probenecid. The experimental time courses of QUIN and HVA following intrastriatal infusion of probenecid were then compared to those predicted from models of microdialysis in which the transport of these compounds remained identical to that of control animals except for an assumed inhibition of active microvascular efflux (i.e resetting of the control efflux rate constant to the control influx rate constant) in the presence of probenecid. Prediction agreed quantitatively with experiment, suggesting that the low levels of QUIN in the brain are maintained by the action of the same probenecid- sensitive efflux pump that is responsible for maintaining low brain concentrations of neurotransmitter acid metabolites. (This is a continuation of Intramural Research Project Z01-RR-10482-02 BEI.)
| Kita, T; Heyes, M P; Morrison, P F et al. (1999) Labeled kynurenine pharmacokinetic modeling studies in gerbils. Nonequilibrium between infused and endogenous kynurenine. Adv Exp Med Biol 467:315-20 |
| Morrison, P F; Morishige, G M; Beagles, K E et al. (1999) Quinolinic acid is extruded from the brain by a probenecid-sensitive carrier system: a quantitative analysis. J Neurochem 72:2135-44 |
