METABOLISM OF DIAZEPAM IN RAT, DOG, AND MAN

Abstract

Diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, labeled with H3 in the 5-phenyl ring was synthesized and administered to rats, dogs and 2 human subjects. One hour after a rat received a 0.6-mg/kg i.p. dose the highest levels of radioactivity were in the liver and perirenal fat, while the lowest concentration of H3 was in the brain. After 48 hours relatively low levels of radioactivity were detectable in the liver, kidney, testes, and carcass, and the rat had excreted 22% of the dose in the urine and 57% in the feces. Oral administration of the same dose also resulted in the fecal excretion of over half of the administered radioactivity. In 2 dog experiments (VaD-1 and VaD-2) 1 mg/kg of H3-diazepam was given i.v. and an average of 61% of the dose was excreted in the urine and 34% in the feces. When the i.v. dose was increased to 10 mg/kg (VaD-3 and VaD-4) the average urinary excretion decreased to 40% of the dose and the average fecal excretion remained at 35% of the dose. Ether-extracted metabolites of dog (VaD-2) blood which fell off with a half-life of 2 hours consisted of a mixture of intact diazepam and the N-desmethyl analog, 7-chloro-1,3-dihydro- 5-phenyl-2H-1,4-benzodiazepin-2-one (compound IV). At the 10-mg/kg dose (VaD-3) this fraction of the blood contained diazepam, which declined rapidly from 1 µg/ml of blood at 1 hour to undetectable levels at 6 hours, and compound IV, which persisted for 12 hours at levels above 1 µg/ml. Also detected in VaD-3 and VaD-4 blood extracts were small amounts of 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one (compound VI, oxazepam). The 2 men (VaH-1 and VaH-2) given 10 mg of H3-diazepam orally excreted an average of 71% of the dose in urine and 10% in the feces. It was estimated that the peak levels of diazepam in blood at 2 to 4 hours averaged 0.07 µg/ml. The fall-off of ether-extractable blood radioactivity in VaH-1 was characterized by a fast component (half-life of 10 hr), a plateau from 1 to 4 days, and then a slow component (half-life of 2.7 days). In VaH-2 the fast component (half-life of 7 hr) was followed immediately by a slow component (half-life of 2.6 days) which was comprised of diazeparn and compound IV. The urine of each of the 3 species contained polar metabolites which, to a very large extent, were hydrolyzed by Glusulase. The deconjugated urinary metabolites of the rat were not identical to diazepam or to 7 analogs and remained unknown. In the dog approximately 80% of this metabolite fraction was identified as compound VI (oxazepam). In man oxazepam accounted for a third of these metabolites while compound IV and the hydroxylated analog of diazepam, 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, each accounted for over 10%. Diazepam metabolism was compared with that of 2 other benzodiazepines, oxazepam and chlordiazepoxide.