Blood Level Distribution Patterns of Diazepam and its Major Metabolite in Man

Abstract

The effect of different diazepam dosage regimens on the blood level patterns of diazepam (I) and of its metabolite N -desmethyl diazepam (II) in man was studied, using specific GLC and TLC techniques, and an ultraviolet assay measuring both components. Single oral doses of diazepam (10 mg.) produced low (0.18–0.21 mcg./ml.) and rapidly declining diazepam (I) blood levels. Repeated daily doses (30 mg.) caused a progressive increase of diazepam (I) levels. The metabolite (II) appeared 24–36 hr. after the first dose, and, thereafter, the levels increased rapidly, approaching those of I. Upon discontinuing the drug after repeated dosing, components I and II disappeared from blood very slowly, II persisting longer than I. The patterns indicated a redistribution into blood of I and II previously stored by tissues. Following chronic massive doses (150–200 mg./day), levels of I averaged 1.60 mcg./ml. (after 1 week of continuous dosage), while 11 continued to increase until an apparent equilibrium was reached at a ratio of I–II of 1:2.5. Only traces of the urinary metabolites, oxazepam and 3 OH-diazepam, were identified in blood.