Kinetics and brain uptake of S 9795, a new xanthine derivate, in rats

Abstract

The relationships between plasma and brain concentrations of S 9795 and its main metabolites after single intravenous doses of S 9795 were examined in rats by high-performance liquid chromatography with UV detection. S 9795 disappeared from plasma and brain almost in parallel, with comparable elimination t1/2 of about 0.8 h, regardless of the dose administered. The volume of distribution was high (about 3 1/kg) but total clearance was also high (about 40 ml/min/kg) and this explains the relatively short plasma and brain t1/2 of the drug in the rat. Among the possible metabolites examined, the N-dearylated metabolite S 10238 rapidly appeared in both plasma and brain. Thereafter, S 10238 was likewise eliminated in parallel from both compartments, although at a slower rate (t1/2 of about 1.4 h) than its parent compound. Norcyclizine, a metabolite resulting from cleavage of the parent drug side-chain, was detected only in the brain and only at the highest dose tested. The brain AUC to plasma AUC ratio was slightly less than 1 for S 9795, about 0.1 for S 10238 and possibly more than 2 for norcyclizine, this latter being present in rat plasma at concentrations below the limits of sensitivity of the method (0.08 nmol/ml). The results indicate that S 9795 and some of its metabolites enter the central nervous system, although to different extents, and support the hypothesis that the lack of central effects of S 9795 is probably the consequence of the poor adenosine brain receptor antagonism by this compound.

Development of a New Reporter Gene System-dsRed/Xanthine Phosphoribosyltransferase-Xanthine for Molecular Imaging of Processes Behind the Intact Blood-Brain Barrier

“…Under these conditions, probe delivery as well as vascular and cell membrane permeability is not limiting. Given a brain distribution volume ( K 1 / k 2 ) of about 1.0 mL/g for xanthine [50] and an influx constant of 0.5-1.0 mL/min/g (as reflected in the blood flow measurements), BBB equilibration ( K 1 and k 2 ) will not significantly impact on the K i measure for values of k 3 that are 0.05 min −1 or less. Under these conditions, the measured K i will be >90% of the K i calculated using the same k 3 and assuming infinite probe equilibration between blood and intracellular water (e.g., K i = K 1 k 3 / k 2 ).…”

“…The best-developed reporter system for nuclear-based imaging, involving the herpes virus type one thymidine kinase (HSV1-tk) and radiolabeled nucleotides [1], does not provide a sufficient solution for reporter imaging in the CNS with an intact BBB. Although HSV1-tk gene-based reporter systems have used different radiolabeled nucleosides as reporter probes, including FIAU [1,38]–[52,43], FGCV [54], FPCV [54], FHPG [53]–[56], and FHBG [5,53,56], these nucleosides and nucleoside analogues do not effectively cross the intact BBB [57]–[59]. However, [ 131 I]- and [ 124 I]-IUdR have been shown to accumulate in the brain tumor tissue that does not contrast-enhance on Tl-weighted MRI after Gd-DTPA administration [60,61], and [ * ]-FIAU does accumulate in HSV1-tk-expressing tumors with a compromised BBB.…”