Disposition and metabolism of lorazepam in the male rat
Schillings, R.T.; Sisenwine, S.F.; Ruelius, H.W.
Drug Metabolism and Disposition the Biological Fate of Chemicals 5(5): 425-435
1977
ISSN/ISBN: 0090-9556 PMID: 20290 Document Number: 120147
After a single intragastric dose of 1 mg of 14C-lorazepam/kg to male rats, maximal plasma and tissue levels of radioactivity were observed within 30 min. Radioactivity in tissues and plasma declined rapidly thereafter. Metabolite patterns were determined for plasma, brain, liver, lung, kidney, heart, testes and urine; the drug was apparently extensively metabolized. The following phase I metabolites were detected: hydroxylorazepam, hydroxymethoxylorazepam, lorazepam dihydrodiol, a novel metabolite, and 2 metabolites formed by ring contraction, namely, 6-chloro-4-(o-chlorophenyl)-2-quinazolinecarboxylic acid and 6-chloro-4-(o-chlorophenyl)-2(1H)-quinazolinone. The presence of lorazepam dihydrodiol indicated that an oxidative biotransformation had proceeded via an arene oxide intermediate. Urinary excretion of the dose amounted to 21.7 .+-. 2.0 (SEM)%, and 68.9 .+-. 1.0% was excreted into feces. Concentrations of lorazepam in plasma and tissues were maximal at 30 min, but tissue levels of lorazepam exceeded those in plasma from 0.5 to 12 h. Only lorazepam was present in brain, indicating that metabolites cannot pass the blood-brain barrier. Appreciable amounts of metabolites of lorazepam were detected in plasma, bile and most tissues, and substantial fractions of the radioactivity in liver, kidney and urine were associated with nonextractable, water-soluble transformation products of unknown structure. The metabolic disposition of lorazepam in the rat is quite different from that in humans, miniature swine, dogs and cats, in which the main biotransformation route is lorazepam glucuronide systhesis. Elimination via the urinary route of excretion predominates in humans, miniature swine and dogs; urinary excretion is about equal to fecal excretion in the cat; whereas in the rat, passage into bile and ultimate fecal elimination are extensive.