The kinetics of tiazofurin uptake by the isolated perfused choroid plexus of the sheep

Tiazofurin (TZF-beta-D-ribofuronosyl thiazole-4-carboxamide, NSC-286193) is a synthetic nucleoside analog with potent antitumor activity. Isolated choroid plexuses (CP) of sheep were perfused in situ and the uptake of [3H]-tiazofurin was determined in relation to the recovery of [14C]-mannitol by means of the paired indicator dilution technique. The maximal uptake of tiazofurin was 8.29 +/- 0.84% and was shown to be both carrier-mediated, sodium-dependent and inhibited by adenosine which suggests that it uses the carrier for endogenous nucleosides. However, the total tiazofurin uptake into the choroid plexus was negligible (0.93 +/- 1.97%) as a result of a high backflux, indicating that tiazofurin is not trapped within the cells of the CP to any significant degree. The kinetics for the uptake into the CP were more favorable than for its passage across the blood-brain barrier with a Km of 7.71 +/- 1.42 microM, a Vmax of 1.30 +/- 0.05 microM/min/g and a negligible constant of a free diffusion (Kd) which suggests that the CP/CSF route may act as an alternative pathway into the brain.