UPTAKE AND BIODISPOSITION OF 2-YLCYANAMIDE-1,3,4-THIADIAZOLE (LY217896) BY RED-BLOOD-CELLS

In man, C-14-2-ylcyanamide-134-thiadiazole (LY217896) accumulates into red blood cells (RBCs) where it is rapidly metabolized. Both in man a nd ex vivo, within a few hours of administration of C-14-LY217896 at l east two intracellular metabolites were detected within the RBCs using HPLC. These metabolites were never detected extracellularly. After 24 h no detectable radioactivity was found in the plasma and all the radi oactivity was detected within the cellular fraction. All radioactivity was identified as a single peak within the RBCs, indicating the metab olite(s) to be highly polar compared to LY217896. Parent LY217896 was never detected within the RBCs at any time point, suggesting transport , either by diffusion or a carrier mediated mechanism, was the rate li miting step. Due to the nature of the preparation it was impossible to separately characterize uptake and biotransformation. Nevertheless, u ptake/biotransformation was found to be temperature sensitive, sodium independent, and energy dependent. Both niacin and vitamin B6, but not nicotinamide, competitively blocked the uptake and subsequent intrace llular metabolism of LY217896.