The biotransformation of [¹⁴C]lormetazepam in dogs, rabbits, rats and rhesus monkeys

Abstract

1. After oral or intravenous doses (0.25 mg/kg) of [¹⁴C]lormetazepam to rats, most of the urinary radioactivity was associated with polar components and < 1% dose was excreted as unconjugated lormetazepam. About 30% of an oral dose was excreted in rat bile as a conjugate of lormetazepam and about 50% dose as polar metabolites. Plasma also contained mainly polar metabolites, and unchanged lormetazepam represented at most 10% of total plasma radioactivity after an oral dose.

2. Almost all the radioactivity in dog, rhesus monkey and rabbit urine, after oral or intravenous doses (0.5–0.7 mg/kg) of [¹⁴C]lormetazepam, was associated with conjugated material. In the dog there were only two major components, conjugates of lormetazepam and lorazepam (N-desmethyl-lormetazepam) which accounted for about 24% and 14% respectively of the oral dose in the 0–24 h urine. The same two conjugated components were also present in dog bile. Conjugated lormetazepam was the only major component in monkey and rabbit urine and accounted for about 60% dose in the 0–24 h urine of each species, while conjugated lorazepam accounted for only about 0.5% and 4% respectively.

3. Dog and monkey plasma contained mostly conjugated material after oral and intravenous doses (0.05–0.07 mg/kg of [¹⁴C]lormetazepam. Dog plasma after an oral dose contained conjugates of both lormetazepam and lorazepam with peak concn. at 1 h of 130 and 47 ng/ml respectively. Concn. of these conjugates in plasma declined with apparent terminal half-lives of about 17 and 27 h respectively after oral doses, and 13 h in both cases after intravenous doses. Conjugated lormetazepam was the only major component in monkey plasma representing a peak concn. of 180 ng/ml at 1 h after an oral dose, and declined with an apparent terminal half-life of about 11 h after oral or intravenous doses.

4. Lormetazepam crosses the placental ‘barrier’ of rabbits: its concn. in the foetus were similar to those in maternal plasma after intravenous doses.