Effect on Acetaminophen Metabolism by Liquid Formulations

Not Applicable

Completed

Conditions: Acetaminophen Metabolism
Drug Metabolism by Excipients
Acetaminophen Poisoning

Interventions: Drug: Acetaminophen solid formulation
Drug: Acetaminophen liquid formulation

Registration Number: NCT01246713

Lead Sponsor: Beth Israel Deaconess Medical Center

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Acetaminophen solid formulation	Acetaminophen solid formulation	Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.
Acetaminophen liquid formulation	Acetaminophen liquid formulation	Subjects in this arm will receive a 15mg/kg dose of a liquid acetaminophen formulation.

Primary Outcome Measures

Name	Time	Method
Acetaminophen Metabolites	8 hours	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.

Secondary Outcome Measures