Summary
The pharmacokinetics and bioavailability of desmethyldiazepam (DMDZ), formed from its precursor clorazepate (CZP) dipotassium, were assessed in a series of 17 healthy volunteers aged 21–66 years. After a single 20-mg intravenous dose of CZP, mean kinetic variables for DMDZ were: volume of distribution, 1.24 l/kg; elimination half-life, 65 h; total clearance, 0.24 ml/min/kg. Among males, DMDZ half-life tended to be prolonged and clearance reduced with age, but this was not true for females. After oral administration of 20 mg CZP, appearance of DMDZ in the circulation was rapid; the mean peak plasma level was 356 ng/ml, reached an average of 0.9 h after dosage. Based on comparison with IV dosage, systemic availability of DMDZ was complete (100% absorption). Ten of the subjects also received a single 20-mg intramuscular dose of CZP. Mean peak DMDZ levels were 290 ng/ml, reaching an average of 2.7 h after dosage. Systemic availability of DMDZ was complete. Elimination half-life of DMDZ for a given individual was highly replicable from trial to trial regardless of the route of CZP administration.
Zusammenfassung
Bei 17 gesunden Versuchspersonen im Alter von 21–66 Jahren wurden Pharmakokinetik und biologische Verfügbarkeit von Desmethyldiazepam (DMDZ) nach Gabe von Dikalium-Clorazepat (DCP) bestimmt. Die kinetischen Variablen für DMDZ nach Gabe einer einmaligen intravenösen 20 mg Dosis von DCP lauten: Verteilungsvolumen 1,24 l/kg; Eliminationshalbwertzeit 65 h; totale Clearance 0,24 ml/min/kg Körpergewicht. Bei den männlichen Versuchspersonen ließ sich eine Tendenz der Zunahme der DMDZ-Halbwertzeiten mit höherem Alter erkennen; eine entsprechende Altersabhängigkeit traf für die weiblichen Versuchspersonen nicht zu. Nach oraler Gabe von 20 mg DCP ließ sich DMDZ rasch im Blut nachweisen; der mittlere maximale Plasmaspiegel von 356 ng/ml wurde 0,9 h nach Applikation gemessen. Im Vergleich zur intravenösen Injektion ergab sich für DMDZ eine systemische Bioverfügbarkeit von 100%. 10 der Versuchspersonen erhielten außerdem eine einmalige intramuskuläre Gabe von 20 mg DCP. Die mittleren maximalen DMDZ-Spiegel lagen bei 290 ng/ml, gemessen im Mittel 2,7 h nach der Injektion. Auch nach intramuskulärer Gabe war die biologische Verfügbarkeit von DMDZ vollständig. Bemerkenswert war die von der Applikationsart unabhängige Beständigkeit der individuellen Halbwertzeiten.
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Supported in part by Grant Oc 10/6–3 from Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, FRG; and by Grant MH-34223 from the United States Public Health Service
Part of doctoral thesis E. Steinhaus, University of Bonn 1982
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Ochs, H.R., Steinhaus, E., Locniskar, A. et al. Desmethyldiazepam kinetics after intravenous, intramuscular, and oral administration of clorazepate dipotassium. Klin Wochenschr 60, 411–415 (1982). https://doi.org/10.1007/BF01735933
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DOI: https://doi.org/10.1007/BF01735933