Effect of renal impairment and hemodialysis on lorazepam kinetics

The effect of renal disease on lorazepam kinetics was assessed in three groups: six normal subjects, six patients with renal impairment, and four functionally anephric patients. Subjects received single 1.5- or 3-mg intravenous and oral doses; eight subjects (four normal and four with renal impairment) also received 0.5-mg oral doses three times a day. Lorazepam and lorazepam glucuronide were determined in plasma, urine, and feces by a highly sensitive gas chromatographic method. After single doses, t1/2 and V beta increased in patients, but Cls in the patients (about 85 ml/min) did not differ significantly from that in normals (71 ml/min). Absorption of oral dose was more than 90% and was not impaired by the disease state. Renal and fecal excretion of intact lorazepam accounted for only about 2% of the dose. The major route of drug elimination was hepatic biotransformation to lorazepam glucuronide, an inactive, nontoxic metabolite eliminated by the kidney. In both the normal and renally impaired groups, about 64% of the dose was recovered as glucuronide in urine and less than 0.4% in feces. Fecal excretion contributed very little to the overall elimination of lorazepam and its glucuronide in all groups. Only 8% of the intact drug was removed by 6-hr hemodialysis, but 40% was removed as glucuronide conjugate. Lorazepam kinetics after subchronic dosing were linear. The difference in Clo between the normal and renally impaired groups was not significant. Since the mean steady-state concentration depends on drug clearance only, and since clearance is not altered, no dosage adjustment appears necessary for patients with renal disease.