Single dose and steady-state pharmacokinetics of adinazolam after oral administration to man

An aqueous solution containing 1 mg of adinazolam mesylate per ml was administered orally as a single dose (40 mg) and with loading doses followed by hourly doses such that final dose rates of 1, 2, and 3 mg h-1 were administered to steady-state. Four subjects exhibited linear steady-state kinetics, while the other four exhibited Michaelis-Menten kinetics, based on measurement by HPLC of both unchanged drug and the major N-demethyl metabolite. The drug is very rapidly absorbed and has an intrinsic clearance of total (bound + free) drug which averaged 2.14 l min-1 based on the steady-state data and 1.17 l min-1 based on the single dose data, but these means do not differ significantly. The apparent metabolite clearance, CLmc/fm (where fm = fraction of adinazolam converted to the N-demethyl metabolite), averaged 0.170 l min-1 based on steady-state data and 0.179 l min-1 based on single dose data and these means do not differ significantly. Pharmacokinetic parameters, such as these clearances, had large intersubject variations. Three types of bioavailabilities were estimated from the data.