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

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.