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.

Trial registration: ClinicalTrials.gov NCT01246713.

Conflict of interest statement

Conflicts of Interest: None for all authors

© The Author(s) 2013.

Figures

Figure 1

Metabolism of acetaminophen. A) P450 metabolism results in NAPQI radical production, which binds and reduces levels of intracellular glutathione leading to decreased redox buffering capacity. NAPQI arylated proteins and initiates toxicity. APAP CYP minor metabolites include APAP-glutathione, APAP-cysteinate and APAP-mercapturate. B) The compartmental model for acetaminophen metabolism used for the pharmacokinetic analysis.

Figure 2

Concentration-time curves for acetaminophen and metabolites. A) Acetaminophen B) Phase II metabolites C) CYP2E1 metabolites (Solid line represents solid preparation, dashed line represents liquid preparation. Error bars represent ± standard error)

Figure 3. Box-whisker plot of formation rate constants