Desmethyldiazepam kinetics after intravenous, intramuscular, and oral administration of clorazepate dipotassium

Abstract

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.

Antipyrine Absorption and Disposition in the Elderly

“…This is consistent with prior reports indicating that withinindividual variations in drug elimination and clearance are far smaller than differ ences observed between individuals [46,[49][50][51]-…”

Clorazepate Dipotassium and Diazepam in Renal Insufficiency: Serum Concentrations and Protein Binding of Diazepam and Desmethyldiazepam

“…In fact, attending physicians judged that the onset o f sedative effects o f clorazepate dipotas sium after single intravenous doses was slow. We similar ly observed that the onset o f sedation after oral doses of clorazepate in healthy volunteers was far more rapid than after intravenous injection o f the same dose [5], This suggests that in vivo conversion o f clorazepate to desme thyldiazepam is required to cause clinical sedative ef fects, and that this conversion may be relatively slow after intravenous dosage. This slow in vivo conversion is not reflected by low serum desmethyldiazepam concentra tions, inasmuch as clorazepate apparently is converted to desmethyldiazepam in the process o f the analytic measu rement [5,8].…”

“…Based on total (free + bound) serum desmethyldiaze- Free clearance, ml/min/kg 6.9 (± 0 .9 ) 2.5 (± 0 . 5 ) pam concentrations, elimination half-life was shorter in patients than in controls, and volume o f distribution was smaller (table 1 ). Total clearance of desmethyldiazepam was similar between groups.…”

“…Concentrations o f desmethyldiaze pam in all samples were determined by electron-capture gas-liquid chromatography [4]. Using iterative nonlinear least squares regres sion techniques as described in detail previously [5], serum desme thyldiazepam levels were used to determine apparent volume of distribution by the area method (Vd), elimination half-life, and total …”

Befindlichkeitsveränderungen in der postoperativen Phase: Droperidol versus Dikaliumclorazepat

“…Die Pharmakokinetik von Dikaliumclorazepat wurde von mehreren Arbeitsgmppen untersucht (1,11,15). Auch fur das Benzodiazepin Iäßt sich eine Diskrepanz zwischen den pharmakokmetischen Daten und der klinischen Wirksamkeit feststellen; es gelten aber umgekehrte Vorzeichen: Wahrend die I-IWZ sehr lang ist (im Mittel 65 Stunden), hält die klinisch beobachtbare Wirkung nur einige Stunden an, wobei allerdings angemerkt sei, dai3 die Beurteilung der klinischen Wirkungsdauer eines an~iol~tisch, kaum hypnogen wirkenden Pharmakons naturgernäi3 nicht leichtfällt.…”