Effect on Acetaminophen Metabolism by Liquid Formulations

Effect on Acetaminophen Metabolism by Liquid Formulations: Do Excipients in Liquid Formulation Prevent Production of Toxic Metabolites?

The purpose of this study is to determine whether excipients in the liquid formulation of acetaminophen prevent the formation of the toxic metabolites of acetaminophen.

Acetaminophen (APAP) poisoning is the most frequent cause of acute hepatic failure in the United States. Toxicity requires cytochrome P-450 bioactivation of APAP. Children are less susceptible to APAP toxicity; the current theory is that they have different metabolism than adults. However, children's liquid preparations of APAP contain excipients which have been shown to inhibit APAP bioactivation in vitro and in rodents. Children tend to ingest liquid preparations, which could potentially explain their decreased susceptibility instead of an intrinsically different metabolism. Further, our review of Poison Center epidemiologic data shows that liquid preparations are less toxic in adults. Our hypothesis is that excipients in liquid preparations inhibit the bioactivation of APAP. The design is a pharmacokinetic cross-over study in humans. Healthy adult subjects will be recruited for administration of therapeutic doses of APAP in capsule and liquid formulations. Plasma via a heplock will be collected at serial time points up to 8 hours and assayed for APAP and its metabolites. After a washout period, subjects will receive the same dose of APAP in the alternate preparation. The pattern of metabolites, indicating the activity of the bioactivating enzymes, will be compared. A significant difference in P-450 metabolites will support the hypothesis and provide preliminary data for studies in patients who have ingested potentially toxic doses of APAP. Ultimately, this work could support development of novel antidotal therapy for APAP overdose.

Area-under-curve from time zero to 8 hours for APAP-cysteinate metabolite. Serum was collected just prior to and at hours 1, 2, 4, 6, and 8 after administration of the APAP dose.

Inclusion Criteria: Healthy volunteer ages 18-40 Not taking any chronic medications Exclusion Criteria: Pregnancy Any history of liver disease Frequent alcohol use (2 or more drinks more than 4 times per week) Unable to provide informed consent

Ganetsky M, Bohlke M, Pereira L, Williams D, LeDuc B, Guatam S, Salhanick SD. Effect of excipients on acetaminophen metabolism and its implications for prevention of liver injury. J Clin Pharmacol. 2013 Apr;53(4):413-20. doi: 10.1002/jcph.24. Epub 2013 Feb 22.