Abstract
14C-Labelled or non-labelled zolpidem hemitartrate, a new hypnotic drug, was given intravenously, intraportally or orally to male rats and its pharmacokinetics was examined. The results are summarized as follows.
1. After intravenous dosing of 3.29 mg/kg of zolpidem hemitartrate, the zolpidem in the plasma disappeared biexponentially with a terminal elimination half-life of 1.11 hours. After oral dosing of 0.66, 3.29 or 16.45mg/kg, zolpidem was absorbed rapidly from the gastrointestinal tract with Tmax of 5 minutes. Linear relationships between AUC, Cmax and the dose were observed, indicating that the pharmacokinetics of zolpidem after oral dosing is linear.
2. The bioavailabilities of zolpidem after oral and intraportal dosing were 45.8 and 46.2%, respectively, suggesting that the oral absorption of 14C-zolpidem was almost complete and that about 54% of oral dose might undergo first-pass matabolism in the liver.
3. Thirty minutes after oral dosing of 3.29mg/kg of 14C-zolpidem hemitartrate, the tissue concentrations of radioactivity in the liver, kidneys, adrenal gland, brown fat, urinary bladder, stomach and small intestine were higher than those in the plasma. 24 hours after dosing, the concentrations of radioactivity in the liver, kidneys, skin and large intestine were 13 ?? 52ng eq/g, but no radioactivity was detected in the other tissues.
4. M-I, a carboxylic acid derivative of zolpidem, was a main metabolite in the plasma, urine, feces and bile of rats. This shows that the main metabolic pathway of zolpidem in rats is methyl oxidation on the phenyl moiety leading to alcohol and carboxylic acid derivatives.
5. 23.7 % of the dosed radioactivity was excreted in the urine and 74.2% in the feces up to 120 hours after oral dosing. Sixty seven % of the dosed radioactivity was excreted in the bile of bile-duct cannulated rats up to 48 hours after oral dosing. Thus, the principal excretion route of radioactivity in rats was the feces via the bile.
