Previous experimentation has shown that quinolinic acid (QA) is characterized by a microvascular efflux rate constant that is about three-fold the influx rate constant. Microdialysis experiments have been conducted that demonstrate that this high rate of efflux is due to the presence of a probenecid-sensitive pump acting on QA. Probenecid administered at 10mM into the brain compartment via an in vivo microdialysis probe implanted in the striatum caused a progressive elevation in both QA and homovanillic acid concentrations in the extracellular fluid compartment. A transient model of QA microdialysis transport accounting for both local and plasma sources of compound was developed and parameterized using rate constants obtained from normal brain. This model accounted quantitatively for the rise in QA levels after reassignment of the normal efflux rate to the normal influx rate just after the initiation of probenecid delivery. Attainment of inhibitory levels of probenecid throughout the QA sampling volume soon after initiation of 10mM probenecid infusate flow was shown to be consistent with microdialysis transport predictions. A microvascular clearance rate for probenecid itself was derived from its extraction efficiency using the steady state microdialysis model of Bungay et al 1990. Other studies have been conducted on kynurenine (a QA precursor) to characterize the relative importance of its in vivo synthesis in the brain versus its transport into the brain from plasma in both normal and immune-activated gerbils. These studies are conducted to ascertain whether systemically synthesized kynurenine (KYN) might always be the ultimate determinant of quinolinic acid concentrations in brain because of its potentially rapid microvascular transport across the brain capillary endothelium. A pharmacokinetic model for KYN concentration in the brain has been developed that allows the percentage contributions from local in vivo synthesis and plasma to be computed from the brain tissue and plasma concentrations of normal and isotopically substituted KYNs. - quinolinic acid, kynurenine, microdialysis, probenecid, blood- brain-barrier
| 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 |
