title: Effect of excipients on acetaminophen metabolism and its implications for prevention of liver injury.
abstract: Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen, primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15 mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protective effect of this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially be developed if co-formulated with a CYP2E1 inhibitor.
authors: Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Michael
authors: M
authors: Ganetsky
authors: Mark
authors: M
authors: Böhlke
authors: Luis
authors: L
authors: Pereira
authors: David
authors: D
authors: Williams
authors: Barbara
authors: B
authors: LeDuc
authors: Shiva
authors: S
authors: Guatam
authors: Steven D
authors: SD
authors: Salhanick
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D019540:Area Under Curve; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D018592:Cross-Over Studies; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004304:Dosage Forms; D005079:Excipients / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D019946:Propylene Glycol / Q000008:administration & dosage* / Q000097:blood; D013431:Sulfates / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004304:Dosage Forms; D005079:Excipients; D013431:Sulfates; D000082:Acetaminophen; D019946:Propylene Glycol; C037386:acetaminophen glucuronide; C048094:acetaminophen mercapturate