The absorption, distribution and excretion of [14C]lormetazepam in dogs, rabbits, rats and rhesus monkeys

Abstract

Oral doses of [14C]lormetazepam [7-chloro-5-(2''-chlorophenyl)-3-hydroxy-1-methyl-2,3-dihydro-1H-1,4-benzodiazepine-2-one] (0.05-0.25 mg/kg) were rapidly and almost completely absorbed by female dogs, rabbits, rats and rhesus monkeys. Elimination of 14C was rapid and similar after oral or i.v. doses. Rats excreted most of the dose in the feces (76%), but dogs, rabbits and monkeys excreted it in the urine (60, 85 and 80%, respectively). The urinary excretion half-lives [t1/2] of 14C from monkeys (.apprx. 10 h), rabbits (.apprx. 12 h), dogs (.apprx. 14 h) and rats (.apprx. 8 h) paralleled the rate of decline of plasma concn. [concentration] of 14C. Biliary excretion of lormetazepam and/or its metabolites occurred in rats (83%), dogs (48%) and possibly to a lesser extent in the other 2 spp. Enterohepatic circulation of 14C in rat was extensive (47%), but not of long duration and probably occurred in dog and rabbit. Mean peak plasma concn. of 14C in dogs, rabbits, rats and monkeys of 190, 29, 42 and 280 ng eq/ml, respectively, were reached at 1.5, 1, 0.5 and 1 h. A.U.C. [area under the concentration time curve] values after oral and i.v. doses were similar in dogs, rats and monkeys. In these species, plasma concn. declined biphasically with t1/2 values of .apprx. 15, 14 and 11 h, respectively. Concn. of 14C in rat tissues, particularly in blood cells, liver, kidneys and gut, were several times greater than those in plasma after single or multiple oral doses. Some accumulation in tissues occurred after multiple doses, presumably due to accumulation of 14C in blood cells. Transplacental transfer of 14C into fetuses of rats or rabbits was low. In rabbits, maternal:fetal concn. ratios ranged between 9 and 26:1 after oral or i.v. doses. The excretion (rats and dogs), or plasma 14C concn.-time profiles (dogs), were not altered during multiple oral doses for 21 days.