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Diazepam versus lorazepam: relationship of drug distribution to duration of clinical action.

Eight healthy volunteers received single intravenous doses of diazepam and lorazepam on two separate occasions. Kinetic parameters of drug distribution and clearance were determined by measurement of multiple plasma concentrations following each dose. Elimination half-life for diazepam averaged 51.2 hr, as compared with 15.7 hr for lorazepam. However, after correction for individual differences in protein binding (mean free fraction 1.5% for diazepam versus 10.1% for lorazepam), the volume of distribution of unbound diazepam (mean 133 liter/kg) was more than 10 times larger than that of lorazepam (mean 12 liter/kg). This is consistent with in vivo measurements of lipid solubility indicating that diazepam has a much larger octanol/water partition coefficient than lorazepam. Thus, the shorter duration of action of a single intravenous dose of diazepam as compared with lorazepam, despite the much longer half-life of diazepam, is explained by the more extensive tissue distribution of unbound diazepam.