Effect on Acetaminophen Metabolism by Liquid Formulations

Condition(s) targeted: Acetaminophen Metabolism; Acetaminophen Poisoning; Drug Metabolism by Excipients

Intervention: Acetaminophen liquid formulation (Drug); Acetaminophen solid formulation (Drug)

Phase: N/A

Status: Completed

Sponsored by: Beth Israel Deaconess Medical Center

Official(s) and/or principal investigator(s):
Michael Ganetsky, MD, Principal Investigator, Affiliation: Beth Israel Deaconess Medical Center

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.

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

Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label

Primary outcome: Acetaminophen Metabolites

Detailed description: 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.

Minimum age: 18 Years. Maximum age: 40 Years. Gender(s): Both.

Criteria:

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

Harvard - Thorndike Clinical Research Center at Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, United States

Starting date: December 2010
Last updated: March 26, 2013