1978 年 98 巻 6 号 p. 720-736
The metabolic fate of Prazepam (PZ), (7-chloro-1-cyclopropylmethyl-1, 3-dihydro-5-phenyl-2H-1, 4-benzodiazepin-2-one) was studied in rats. After oral or intravenous administration of 5-14C-PZ, the radioactivity was detected in various tissues, indicating extensive uptake of this compound. A higher level of the radioactivity was seen in the liver, small intestine, stomach, adrenal, and kidneys. After oral administration, the radioactivity level in the brain was nearly comparable to that in the blood. In the case of intravenous administration, however, the level in the brain was several times higher than that in the blood. In each route of administration, fecal excretion mostly resulting from biliary excretion was the major elimination route of this drug. A major metabolite in the urine was 4'-hydroxydesalkylprazepam (4'-HDPZ) sulfate which was also found in the bile. Other major metabolites in the bile were 3-hydroxyprazepam (HPZ) glucuronide and metabolite A which was present as free and conjugated forms. Most of the biliary metabolites were found in the feces as a free form with the unchanged drug. Metabolite A was isolated from the bile and identified as 3'-hydroxydesalkylprazepam (3'-HDPZ). Major metabolites in the plasma, liver, and kidneys were desalkylprazepam (DPZ), oxazepam (OX), 4'-HDPZ, and its sulfate. In the brain, DPZ and OX were the major metabolites, but a small amount of the unchanged drug and HPZ was also detected. These results suggest that the main reactions in the PZ metabolism are C3-hydroxylation to HPZ and N-dealkylation to DPZ followed by aromatic hydroxylation to 3'- and 4'-HDPZ or C3-hydroxylation to OX. These metabolic patterns were not altered after a repeated administration. The relationship between the pharmacological activity and metabolism of this drug is also discussed.