Kinetics and biotransformation of lormetazepam. II. Radioimmunologic determinations in plasma and urine of young and elderly subjects: first-pass effect.

A specific and sensitive radioimmunoassay has been developed for a new benzodiazepine, lormetazepam. After intravenous injection, lormetazepam levels in plasma fell in three (alpha, beta, gamma) dispositional phases, two of them (alpha, beta) mainly reflecting different distribution processes. The terminal (gamma) phase correlated well with the rate of renal elimination of glucuronides. Oral doses were completely absorbed with widely varying absorption half-lifes (t1/2s) amounting to an average of 0.67 +/- 0.53 hr. Dose-dependent maximum plasma levels were reached in about 2 hr. Lormetazepam undergoes first-pass metabolism of about 20% of an oral dose. Total clearance was in the range of 200 ml/min. There was a trend toward slower terminal disposition phase in elderly subjects. In younger subjects, the terminal phase t1/2 was about 10 hr. Lormetazepam glucuronide peak plasma levels were reached by about 6 hr. Thereafter, the level fell in one (elimination) phase, with a t1/2 of 12 hr in young subjects and with a significantly (p < 0.05) different t1/2 of about 20 hr in the elderly. Renal clearance was calculated as about 30 to 40 ml and did not show an age-dependent difference. Recovery of lormetazepam glucuronide with urine amounted to 70% to 80% of the dose during 72 hr after intravenous injection in both age groups.