Metabolic Fate of Zolpidem. (II). Pharmacokinetics of Zolpidem in Rats after Multiple Oral Dosing.

Abstract

The 14C-labelled compound of zolpidem hemitartrate, a new hypnotic drug, was given orally in a dose of 3.29mg/kg to male rats once a day for a maximum of 28 days, and its absorption, distribution, metabolism and excretion were examined. The results are summarized as follows. 1. Area under the blood radioactivity-time curves (AUCs) up to 24 hours after the 1st, 7th, 14th, 21st and 28th dosing were 1.74, 1.35, 1.92, 1.73 and 2.14μg eq.hr/ml respectively. Since there was no the difference among AUCs after the 14th, 21st and 28th dosing, the blood radioactivity was considered to have reached a steady state. The increase of AUCs during multiple dosing was of low extent because those after the 14th and 28th dosing were only 1.1 and 1.2 times higher than those after the 1st dosing. 2. Tissue to plasma concentration ratios of radioactivity after the 14th or 21st dosing were almost constant in many tissues including the blood, lung, liver, kidneys and skin whose the concentrations of radioactivity were higher than in the plasma. This showed that the tissue radioactivity was probably reaching a steady state after the 14th or 21st dosing. 3. The disappearance of radioactivity after the 28th dosing was slow er in the kidneys, spleen and skin than that in the plasma. Seventy two hours after the last dosing, however, the concentrations of radioactivity in these tissues were less than 1 % of the 5 min-value, and no radioactivity was detected at 70 days. 4. After the 28th dosing, the zolpidem was not detected in the urine and feces, and M-I accounted for 57.4 and 59.0% of radioactivity excreted in the urine and feces, respectively. Each amount of M-II ?? M-V in the excreta was 1/10 of that of M-I. The metabolism of zolpidem was unaffected by multiple oral dosing (28 times). 5. Urinary and fecal excretion of radioactivity was almost constant during multiple oral dosing.