METABOLISM AND DISTRIBUTION OF 1-[C-14]ALPRAZOLAM IN RATS

Using C-14-labeled alprazolam (1-[C-14]APZ) as a model for 1-[C-11]APZ, we evaluated the tissue distribution of total radioactivity and assessed the contribution of the polar metabolites of APZ (alpha-hydroxmethyl- and 4-hydroxy-APZ) to radioactivity levels in the plasma and brains of rats over the course of 1 h. The biodistribution data showed that the uptake of radioactivity by rat brain was 0.31 % of the injected dose per gram of tissue weight at 10 min postinjection. Pretreating rats reduced the levels in brain to 0.21 % of the injected dose at 1 0 min but had little effect on the distribution of radioactivity in plasma and other tissues studied. Analysis of the metabolites in plasma and brain homogenates by an extraction-thin-layer chromatography-liquid scintillation method revealed that >94% of the radioactivity in the rat brain was due to 1-[C-14]APZ over the course of 1 h. APZ, therefore, is stable to metabolic transformations in the rat brain, and the polar metabolites are readily conjugated and excreted so that their cerebral uptake is minimal.