Single- and multiple-dose kinetics of oral lorazepam in humans: the predictability of accumulation

Six healthy volunteers participated in single- and multiple-dose pharmacokinetic studies of oral lorazepam. Following single 4-mg oral doses, peak plasma lorazepam concentrations ranging from 40 to 70 ng/ml were reached within 3 hr of the dose. Values of absorption half-life averaged 25 min (range 10.3-42.7 min), and elimination half-life (t1/2 beta) averaged 14.2 hr (range 8.4-23.9 hr). During 15 consecutive days of 3 mg per day administered in divided doses, accumulation to the steady-state condition was complete within several days of the initiation of therapy. Values of accumulation half-life (mean 21.1 hr) were slightly longer than t1/2beta, and the two were not well correlated. Observed accumulation ratios (mean 1.88) were very close to those predicted from the single-dose study (mean 1.77), but the correlation between the two (r = 0.51) was not significant in the small sample size. "Washout" half-life values (mean 14.9 hr) were highly correlated with t1/2beta (r = 0.92). Clearance of a single intravenous dose of antipyrine determined prior to the multiple-dose lorazepam study (mean 0.86 ml/min/kg) was essentially identical to that determined after the study (mean 0.87 ml/ min/kg). Overall, the rate and extent of lorazepam accumulation during multiple dosage were reasonably well predicted by the single-dose kinetic study. However, accurate prediction for any specific individual was not always achieved. Stimulation or inhibition by lorazepam of its own clearance probably does not explain imprecise prediction, since single-dose t1/2beta and washout half-life values were essentially identical. Furthermore, chronic lorazepam exposure has no apparent effect on hepatic hydroxylation capacity as measured by clearance of exogenously administered antipyrine.