Population pharmacokinetics of lorazepam and midazolam and their metabolites in intensive care patients on continuous venovenous hemofiltration.
BACKGROUND
The objective is to study the population pharmacokinetics of lorazepam and midazolam in critically ill patients with acute renal failure who are treated with continuous venovenous hemofiltration (CVVH).


METHODS
Twenty critically ill patients with acute renal failure on CVVH therapy were administered either lorazepam (n = 10) or midazolam (n = 10) by continuous infusion. CVVH was performed with an ultrafiltrate flow of 2 L/h with filtrate substitution in the predilution or postdilution mode. Blood flow through the 1.9-m 2 cellulose triacetate membrane filter was 180 mL/min. For 48 hours, multiple blood and ultrafiltrate samples were obtained for determination of concentrations of the drug and its metabolites.


RESULTS
The pharmacokinetics of lorazepam is described best by a 1-compartment model. No significant covariates were identified. Total-body clearance was 6.4 L/h, and volume of distribution was 376 L. Ultrafiltration clearance was 0.31 L/h, equivalent to approximately 5% of total clearance. Average degree of plasma protein binding was 82.9% for lorazepam, with a sieving coefficient of 0.16 +/- 0.03. For lorazepamglucuronide, degree of plasma protein binding was 39.5%, and sieving coefficient was 0.48 +/- 0.07. The pharmacokinetics of midazolam is described best by a 1-compartment model. No significant covariates were identified. Total-body clearance was 8.5 L/h, and volume of distribution was 157 L. Clearance by ultrafiltration was 0.055 L/h, equivalent to approximately 0.7% of total clearance. Average degree of plasma protein binding was 95.8%, with a sieving coefficient of 0.04 +/- 0.03. For the metabolite 1-hydroxymidazolamglucuronide, average degree of plasma protein binding was 43.4%, with a sieving coefficient of 0.45 +/- 0.06.


CONCLUSIONS
Neither lorazepam nor midazolam is removed efficiently by CVVH. CVVH contributes significantly to the removal of the glucuronide metabolites lorazepamglucuronide and 1-hydroxymidazolamglucuronide.
Swart
Eleonora L
EL
Department of Pharmacy, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. el.swart@vumc.nl <el.swart@vumc.nl>
de Jongh
Joost
J
Zuideveld
Klaas P
KP
Danhof
Meindert
M
Thijs
Lambertus G
LG
Strack van Schijndel
Robert J M
RJ
D058186:Acute Kidney Injury / Q000097:blood / Q000628:therapy; D000328:Adult; D000368:Aged; D016292:Procedural Sedation / Q000379:methods; D004334:Drug Administration Schedule; D004341:Drug Evaluation / Q000379:methods; D005260:Female; D006440:Hemofiltration / Q000379:methods*; D006801:Humans; D008140:Lorazepam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D008962:Models, Theoretical; D009102:Multiple Organ Failure / Q000097:blood; D012121:Respiration, Artificial / Q000379:methods; D012122:Ventilators, Mechanical
D008140:Lorazepam; C031290:lorazepam glucuronide; D008874:Midazolam