Abstract
The benzodiazepine tetrazepam is primarily muscle relaxant with comparably lower central sedating effects and is therefore commonly prescribed for muscle spasms of different origins. To evaluate tetrazepam metabolism, a study was conducted with ten healthy volunteers. Blood and urine samples were regularly collected after the intake of 50 mg tetrazepam. Toxicological analyses revealed that tetrazepam is also metabolized to diazepam and further to nordazepam, which has not yet been reported. Tetrazepam and diazepam could be detected in urine samples at least 72 h after intake, the diazepam concentration being 33% (±14% SD), on average, of the tetrazepam concentration. On the basis of three case histories, the importance of the detection of these newly described metabolites is shown as necessary to prevent false accusations and potential negative legal consequences for examined persons.
Similar content being viewed by others
References
Keane PE, Simiand J, Morre M, Biziere K (1988) Tetrazepam: a benzodiazepine which dissociates sedation from other benzodiazepine activities. I. Psychopharmacological profile in rodents. J Pharmacol Exp Ther 245:692–698
Keane PE, Bachy A, Morre M, Biziere K (1988) Tetrazepam: a benzodiazepine which dissociates sedation from other benzodiazepine activities. II. In vitro and in vivo interactions with benzodiazepine binding sites. J Pharmacol Exp Ther 245:699–705
Milanov I (1992) Mechanisms of tetrazepam action on spasticity. Acta Neurol Belg 92:5–15
Lobisch M, Schaffler K, Wauschkuhn H, Nickel B (1996) Clinical pilot study of the myogenic effects of flupirtine in comparison to tetrazepam and placebo (in German). Arzneimittelforschung 46:293–298
Simiand J, Keane PE, Biziere K, Soubrie P (1989) Comparative study in mice of tetrazepam and other centrally active skeletal muscle relaxants. Arch Int Pharmacodyn Ther 297:272–285
Perez-Guerrero C, Suarez J, Herrera MD, Marhuenda E (1997) Vasodilating effects of tetrazepam in isolated vascular smooth muscles: comparison with cromakalim and diltiazem. Pharmacol Res 36:237–242
Pellkofer M, Paulig M (1989) Comparative double-blind study of the effectiveness and tolerance of baclofen, tetrazepam and tizanidine in spastic movement disorders of the lower extremities (in German). Med Klin (Munich) 84:5–8
Rote Liste (2005) Tetrazepam. Rote Liste Win 2005/II version 4.2 Rote Liste Service GmbH
Baumgartner MG, Cautreels W, Langenbahn H (1984) Biotransformation and pharmacokinetics of tetrazepam in man. Arzneimittelforschung 34:724–729
Dussy FE, Hamberg C, Briellmann TA (2005) Quantification of benzodiazepines in whole blood and serum. Int J Legal Med Oct 12:1–8
Maurer H, Pfleger K (1987) Identification and differentiation of benzodiazepines and their metabolites in urine by computerized gas chromatography–mass spectrometry. J Chromatogr 422:85–101
Staak M, Sticht G, Saternus KS, Kaferstein H (1982) Pharmacokinetic studies following administration of tetrazepam in rhesus monkeys. Beitr Gerichtl Med 40:323–328
Bun H, Philip F, Berger Y, Necciari J, Al Mallah NR, Serradimign A, Cano JP (1987) Plasma levels and pharmacokinetics of single and multiple dose of tetrazepam in healthy volunteers. Arzneimittelforschung 37:199–202
Staak M, Sticht G, Kaferstein H, Norpoth T (1984) Pharmacokinetics and metabolite pattern of tetrazepam and chlordesmethyldiazepam. Beitr Gerichtl Med 42:75–79
Schulz M, Schmoldt A (2003) Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Pharmazie 58:447–474
Geister U, Gaupp M, Arnold P, Schaarschmidt D, Doser K (2000) Bioavailability investigation of two different oral formulations of tetrazepam. Arzneimittelforschung 50:328–332
Concheiro M, Villain M, Bouchet S, Ludes B, Lopez-Rivadulla M, Kintz P (2005) Windows of detection of tetrazepam in urine, oral fluid, beard, and hair, with a special focus on drug-facilitated crimes. Ther Drug Monit 27:565–570
Musshoff F, Dettmeyer R, Madea B (1998) Death in the bathtub—rectal drug administration. Arch Kriminol 201:80–86
Boccardi G, Deleuze C, Gachon M, Palmisano G, Vergnaud JP (1992) Autoxidation of tetrazepam in tablets: prediction of degradation impurities from the oxidative behavior in solution. J Pharm Sci 81:183–185
Hammad MA, Muller BW (1998) Solubility and stability of tetrazepam in mixed micelles. Eur J Pharm Sci 7:49–55
Guengerich FP (1991) Reactions and significance of cytochrome P-450 enzymes. J Biol Chem 266:10019–10022
Porter TD, Coon MJ (1991) Cytochrome P-450. Multiplicity of isoforms, substrates, and catalytic and regulatory mechanisms. J Biol Chem 266:13469–13472
Schütz H (1989) Benzodiazepines II. A handbook, 1st edn. Springer, Berlin Heidelberg New York, p 32
He YA, Roussel F, Halpert JR (2003) Analysis of homotropic and heterotropic cooperativity of diazepam oxidation by CYP3A4 using site-directed mutagenesis and kinetic modeling. Arch Biochem Biophys 409:92–101
Steentoft A, Worm K, Pedersen CB, Sprehn M, Mogensen T, Sorensen MB, Nielsen E (1996) Drugs in blood samples from unconscious drug addicts after the intake of an overdose. Int J Legal Med 108:248–251
Kaa E, Teige B (1993) Drug-related deaths during the 1980s. A comparative study of drug addict deaths examined at the institutes of forensic medicine in Aarhus, Denmark and Oslo, Norway. Int J Legal Med 106:5–9
Favretto D, Frison G, Maietti S, Ferrara SD (2006) LC-ESI-MS/MS on an ion trap for the determination of LSD, iso-LSD, nor-LSD and 2-oxo-3-hydroxy-LSD in blood, urine and vitreous humor. Int J Legal Med (in press) DOI 10.1007/s00414-006-0078-x
Acknowledgements
The authors would like to thank Dr. Herbert Oberacher for valuable discussions and Mrs. Elisabeth Unterdorfer and Mr. Karl-Heinz Pramstrahler for their technical support within the laboratory.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pavlic, M., Libiseller, K., Grubwieser, P. et al. Medicolegal aspects of tetrazepam metabolism. Int J Legal Med 121, 169–174 (2007). https://doi.org/10.1007/s00414-006-0118-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00414-006-0118-6