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

Abstract

1. Oral doses of [¹⁴C]lormetazepam (0.05–0.25mg/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.

2. Rats excreted most of the dose in the faeces (76%), whereas dogs, rabbits and monkeys excreted it in the urine (60, 85 and 80% respectively. The urinary excretion half-lives of ¹⁴C from monkeys (c. 10 h), rabbits (c. 12 h), dogs (c. 14 h) and rats (c. 8 h) paralleled the rate of decline of plasma concn. of ¹⁴C.

3. Biliary excretion of lormetazepam and/or its metabolites occurred in rats (83%), dogs (48%) and possibly to a lesser extent in the other two species. Enterohepatic circulation of ¹⁴C in rat was extensive (47%), but not of long duration, and probably occurred in dog and rabbit.

4. Mean peak plasma concn. of ¹⁴C in dogs, rabbits, rats and monkeys of 190, 29, 42 and 280 ng equiv./ml respectively were reached at 1.5, 1, 0.5 and 1 h. A.U.C. values after oral and i.v. doses were similar in dogs, rats and monkeys. In these species, plasma concn. declined biphasically with t_1/2 values of about 15, 14 and 11 h respectively.

5. 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 partly because of accumulation of ¹⁴C in blood cells.

6. Transplacental transfer of ¹⁴C into foetuses of rats or rabbits was low. In rabbits, maternal: foetal concn. ratios ranged between 9 and 26 : 1 after oral or i.v. doses.

7. The excretion (rats and dogs), or plasma ¹⁴C concn.-time profiles (dogs), were not altered during multiple oral doses for 21 days.