The pharmacokinetics and extracorporeal removal of N-acetylcysteine during renal replacement therapies.
OBJECTIVE
Acetaminophen-induced fulminant hepatic failure is associated with acute kidney injury, metabolic acidosis, and fluid and electrolyte imbalances, requiring treatment with renal replacement therapies. Although antidote, acetylcysteine, is potentially extracted by renal replacement therapies, pharmacokinetic data are lacking to guide potential dosing alterations. We aimed to determine the extracorporeal removal of acetylcysteine by various renal replacement therapies.


METHODS
Simultaneous urine, plasma and effluent specimens were serially collected to measure acetylcysteine concentrations in up to three stages: before, during and upon termination of renal replacement therapy. Alterations in pharmacokinetics were determined by applying standard pharmacokinetic equations.


RESULTS
Over 2 years, 10 critically ill patients in fulminant hepatic failure requiring renal replacement therapy coincident with acetylcysteine were consecutively enrolled. All 10 patients required continuous venovenous hemofiltration (n = 10) and 2 of the 10 also required hemodialysis (n = 2). There was a significant alteration in the pharmacokinetics of acetylcysteine during hemodialysis; the area under the curve (AUC) decreased 41%, the mean extraction ratio was 51%, the mean hemodialytic clearance was 114.01 ml/kg/h, and a mean 166.75 mg/h was recovered in the effluent or 41% of the hourly dose. Alteration in the pharmacokinetics of acetylcysteine during continuous venovenous hemofiltration did not appear to be significant: the AUC decreased 13%, the mean clearance was 31.77 ml/kg/h and a mean 62.12 mg/h was recovered in the effluent or 14% of the hourly dose.


CONCLUSIONS
There was no significant extraction of acetylcysteine from continuous venovenous hemofiltration. In contrast, there was significant extracorporeal removal of acetylcysteine during hemodialysis. A reasonable dose adjustment may be to double the IV infusion rate or possibly supplement with oral acetylcysteine during hemodialysis.
a Division of Medical Toxicology, Department of Emergency Medicine , Icahn School of Medicine at Mount Sinai , New York , NY , USA.
Stephanie H
SH
Hernandez
b St. John's University College of Pharmacy and Health Sciences , Queens , NY , USA.|c New York City Poison Control Center, New York City Department of Health , New York , NY , USA.|d Division of Medical Toxicology, Department of Emergency Medicine , New York University School of Medicine , New York , NY , USA.
Maryann
M
Howland
e Division of Liver Diseases, Department of Internal Medicine , Icahn School of Medicine at Mount Sinai , New York , NY , USA.
Thomas D
TD
Schiano
c New York City Poison Control Center, New York City Department of Health , New York , NY , USA.|d Division of Medical Toxicology, Department of Emergency Medicine , New York University School of Medicine , New York , NY , USA.
Robert S
RS
Hoffman
D000082:Acetaminophen / Q000506:poisoning; D000111:Acetylcysteine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D058186:Acute Kidney Injury / Q000097:blood / Q000209:etiology / Q000628:therapy* / Q000652:urine; D000931:Antidotes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006440:Hemofiltration; D006801:Humans; D007262:Infusions, Intravenous; D011446:Prospective Studies; D006435:Renal Dialysis; D014018:Tissue Distribution
D000931:Antidotes; D000082:Acetaminophen; D000111:Acetylcysteine
Continuous venovenous hemofiltration; Fulminant hepatic failure; Hemodialysis; N-acetylcysteine; Pharmacokinetics; Renal replacement therapy