Formycin B Elimination from the Cerebrospinal Fluid of the Rat

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Abstract
The goal of this study was to determine whether specific transport systems are involved in nucleoside elimination from the cerebrospinal fluid (CSF). First, in vitro studies were carried out in isolated choroid plexus tissue slices from rat to ascertain the mechanisms of transport of formycin B, a model nucleoside analogue. 3H-Formycin B accumulated against a concentration gradient in the presence of an Na+ gradient in the isolated ATP-depleted choroid plexus tissue slices. This accumulation was reduced by high concentrations of unlabeled formycin B. Nitrobenzylthioinosine (NBMPR), an equilibrative nucleoside transport inhibitor, inhibited the uptake of formycin B in the absence of an Na+ gradient. These data suggest that both equilibrative and secondary active Na+-nucleoside transport systems are present in rat choroid plexus. In vivo, formycin B, together with inulin as a bulk flow marker, was injected into the lateral ventricle of the anesthetized rat with the aid of a stereotaxic device, and CSF was sampled from the cisterna magna at various times after injection. Twelve rats were randomized and divided into a low- and a high-dose group. The CSF clearance (CLCSF) of formycin B was significantly higher than the CLCSF of inulin in both animal groups (P < 0.01), indicating that formycin B is cleared from CSF by a pathway(s) in addition to bulk flow. Formycin B CLCSF was significantly lower in the high-dose group than in the low-dose group (P < 0.05), suggesting a saturable CSF elimination. The CLCSF of formycin B was also significantly reduced in animals treated with NBMPR (P < 0.05). These data are consistent with the in vitro studies and collectively suggest that formycin B is eliminated from the CSF by a pathway(s) in addition to bulk flow. At least one pathway is saturable and may represent an equilibrative nucleoside transport system which can be inhibited by NBMPR.