Summary
The pharmacokinetics and metabolism of the new benzodiazepine lormetazepam were investigated in five male volunteers using thel4C-abelled drug (position 5). Lormetazepam was administered intravenously and orally, at a dose of 0.2 and 2 mg respectively, to each of the test subjects.
Measurements of total radioactivity showed that the drug was absorbed completely and eliminated almost exclusively by the renal route. Maximum plasma level of active ingredient and total radioactivity were observed about 2 hours and 5 hours following oral administration. As early as 30 min following oral administration, concentration of active ingredient amounted to 80% of the maximum values. After both treatments the terminal half-life of total radioactivity and lormetazepam glucuronide in plasma corresponded to the half-life of elimination in urine of about 13 hours.
After enzymatic hydrolysis with β-glucuronidase/arylsulphatase, an average of 90% of total radioactivity from various urine and plasma samples was extractable with ether. Extracts from plasma contained only unchanged drug, indicating free and conjugated lormetazepam as ingredients of total radioactivity. Extracts from urine could be separated into lormetazepam and its N-demethylation derivative lorazepam. The relative amount of excreted lorazepam conjugate was demonstrated to be time-dependent, probably due to enterohepatic circulation. Since less than 6% of the total dose was demethylated by both routes of administration, it can be assumed that lormetazepam is the active product.
Similar content being viewed by others
References
Oswald I., Adam K., Burrow S. and Idzikowski C. (1979): The effects of two hypnotics on sleep, subjective feelings and skilled performance. In: Passouant P. and Oswald (Edts.) I. Pharmacology in the state of alertness, Oxford: Pergamon Press, 51–63.
Girkin R., Baldock G.A., Chasseaud L.F., Hümpel M., Hawkins D.R. and Mayo B.C. (1980): The absorption, distribution and excretion of14-C-lormetazepamin dogs, rabbits, rats and rhesus monkeys, Xenobiotica, accepted for publication.
Mayo B.C., Hawkins D.R., Hümpel M., Chasseaud L.F., Baldock G.A. and Girkin R. (1980): The biotransformation ofl4C-lormetazepam m dogs, rabbits, rats and rhesus monkeys. For publication.
Sternbach L., Reeder E., Keller O. and Metlesics W. (1961): Quinazoline and 1,4-benzodiazepines, J. Org. Chem.,26, 4488.
Bell S., Sulkowski T., Gochman C. and Childress S. (1962): 1,3-dihydro-2H-1,4-benzodiazepine-2-ones and their 4-oxides, J. Org. Chem., 27,1691.
Hsi R. (1974): Synthesis of carbon-14 labelled 1,4-benzo-diazepine, J. Lab. Comp.,10, 389.
Speck U., Wendt H., Schulze P.E. and Jentsch D. (1976): Bioavailability and pharmacokinetics of cyproterone acetate-14C and ethinylestradiol-3H after oral administration as coated tablet (SH B 209 AB), Contraception,14, 151–163.
Schenelle K. and Garrett E.T. (1973): Pharmacokinetics of the β-adrenergic blocker sotalol in dogs, J. Pharm. Sci.,62, 362–375.
Diem K. and Lentner C. (1975): Documenta Geigy, Stuttgart: Georg Thieme Verlag, 7th Edition, p. 519.
Knowles J.A., Comer W.H. and Ruelius H.W. (1971): Disposition of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4 benzodiazepin-2-one (lorazepam) in humans, Arzneim. Forsch.,21,1055–1059.
Greenblatt D.J., Franke K. and Shader R.I. (1978): Analysis of lorazepam and its glucuronide metabolite by electroncapture gas-liquid chromatography, use in pharmacokinetic studies of lorazepam, J. Chromatogr.,146, 311–320.
Kraus J.W., Desmond P.V., Marshall J.P., Johnson R.F., Schenker S. and Wilkinson G.R. (1978): Effects of aging and liver disease on disposition of lorazepam, Clin. Pharmacol. Ther.,24, 411–419.
Greenblatt D.J., Schillings R.T., Kyriakopoulos A.A., Shader R.I., Sisenwine S.F., Knowles J.A. and Ruelius H.W. (1976): Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral14C-lorazepam, Clin. Pharmacol. Ther.,20, 329–341.
Greenblatt D.J., Joyce T.H., Comer W.H., Knowles J.A., Shader R.I., Kyriakopoulos A.A., Mac Laughlin D.S. and Ruelius H.W. (1977): Clinical pharmacokinetics of lorazepam. II. Intramuscular injection. Clin. Pharmacol. Ther.,21, 222–230.
Greenblatt D.J., Comer W.H., Elliott H.W., Shader R.I., Knowles J.A. and Ruelius H.W. (1977): Clinical pharmacokinetics of lorazepam III. Intravenous injection Preliminary results, J. Clin. Pharmacol.,17, 490–494.
Verbeck R., Tjandramaga T.B., Verbeckmoes R. and de Schepper P.J. (1976): Biotransformation and excretion of lorazepam in patients with chronic renal failure, Brit. J. Clin. Pharmacol.,3,1033–1039.
Humpel M., Nieuweboer B., Milius W. and Wendt H. (1980) : The pharmacokinetics and biotransformation of a new benzodiazepine (lormetazepam) in humans. II. Radioimmunological determinations in plasma and urine of younger and elders volunteers; first-pass-effect, J. Clin. Pharm. Ther. (Accepted for publication).
Düsterberg B. (1978): Personal communication.
Schillings T., Shrader S.R. and Ruelius H.W. (1971): Urinary metabolites of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-on (Lorazepam) in humans and four animal species, Arzneim. Forsch.,21, 1059–1065.
Author information
Authors and Affiliations
Additional information
In part, this investigation will be used in the Ph.D. thesis of M. Kurowski.
Generic name of the active ingredient of the preparation NOCTAMID ® (Schering AG). Chemical name: 7-chloro-5-(2-chlorophenyl)-3-hydroxy-l-methyl-2,3-dihydro-1H-1,4-benzodiazepine-2-one; patented by Wyeth Laboratories, Phil., USA.
Rights and permissions
About this article
Cite this article
Hümpel, M., Illi, V., Milius, W. et al. The pharmacokinetics and biotransformation of the new benzodiazepine lormetazepam in humans I. Absorption, distribution, elimination and metabolism of lormetazepam-5-14C. European Journal of Drug Metabolism and Pharmacokinetics 4, 237–243 (1979). https://doi.org/10.1007/BF03189433
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03189433