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Abstract
1. Blood levels of nimetazepam after oral administration to dogs were relatively low at early periods after dosage and reached peak levels (7.7–7.9 μg equiv./ml) after 8 h. The time course of blood levels was similar after oral administration of its desmethyl derivative (nitrazepam) to dogs. Blood levels of the latter, however, were low compared with nimetazepam and reached a peak (,5–2-6–3 μg equiv./ml) after 4 h.
2. Recoveries of nimetazepam in urine and faeces were 46 and 52% of the dose for 0–24 h, 27 and 34% for 24–48 h and 4 and 6% for 48–72 h, while those of its desmethyl derivative (nitrazepam) were 63 and 71% for 0–24 h, 12 and 21% for 24–48 h and 2 and 3% for 48–72 h.
3. At least four kinds of reaction were involved in the biotransformation of nimetazepam and its desmethyl derivative (nitrazepam): (i) demethylation at N-l (ii) hydroxylation at C-3, (iii) subsequent glucuronic acid conjugation of 3-hydroxy derivatives and (iv) reduction of the nitro group at C-7 to an amino group. Reaction (i) proceeded very rapidly in dogs, so that the blood metabolites of nimetazepam were closely similar to those of nitrazepam. For both drugs, the major blood metabolite was nitrazepam. Reaction (ii) was rapidly followed by reaction (iii), and glucuronides were predominantly excreted in urine. Reaction (iv) as well as reaction (iii) are important in the excretion of both drugs. The subsequent acetylation of 7-amino group, however, did not occur in dogs as it did in mice and rats.