1999 Volume 14 Issue 2 Pages 92-104
The absorption, distribution, metabolism and excretion of radioactivity were investigated in rats after oral administration of 14C-azasetron hydrochloride.
1. Azasetron hydrochloride was mainly absorbed from the small intestine. The extent of absorption was estimated to be more than 91% by the sum of radioactivity excretion in the urine and bile after dosing. The plasma levels of radioactivity showed a maximum (Cmax) within 0.6 hour, and then was eliminated with the terminal half-lives (t1/2Z) of 6.7-8.0 hours after administration of 0.4, 2 and 10 mg/kg doses. No dose-related difference in t1/2Z was observed. The Cmax and the areas under the plasma concentration-time curve increased greater than dose proportionally.
2. Radioactivity distributed rapidly into various tissues, showing a peak level at 1 hour after dosing in most tissues. Radioactivity levels were high in the gut and urinary bladder, followed by the liver, pituitary gland, kidney, submaxillary gland, pancreas and lung. Radioactivities in most tissues at 24 hours after dosing were not detected.
3. Within 48 hours after administration to rats at the doses of 0.4, 2 and 10 mg/kg, total excretion of radioactivity was more than 96%. Radioactivity disappeared rapidly from the body. At 96 hours after administration of 2 mg/kg, radioactivity was not detected in the body. Following administration to bile-duct cannulated rats, urinary excretion increased significantly, and biliary excretion decreased significantly with elevation of the dose. About 24% of radioactivity excreted in the bile was reabsorbed from the intestine via the enterohepatic circulation.
4. No qualitative difference was observed in metabolite pattern in the urine, feces and bile between the dose levels, but a quantitative difference was observed. Following administration to bile-duct cannulated rats, azasetron was excreted primarily as unchanged drug and metabolite M1 in the urine, while primarily as M1 and M3 in the bile. At 10 mg/kg dose, as compared with 0.4 and 2 mg/kg doses, urinary excretion of azasetron increased significantly, and biliary excretion of main metabolites M1 and M3 decreased significantly. The extent of absorption decreased by feeding, but alteration of metabolism was not observed.
5. These findings suggest that the cause of the non-linear pharmacokinetic behavior of 14C-azasetron hydrochloride is due mainly to saturation of a metabolic capacity of azasetron in the liver.
