Acetaminophen Metabolism, Acetaminophen Poisoning, Drug Metabolism by Excipients
Conditions
Keywords
acetaminophen, excipients
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.
Interventions
DRUGAcetaminophen liquid formulation
Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.
DRUGAcetaminophen solid formulation
Subjects in this arm will receive a 15mg/kg dose of a solid acetaminophen formulation.
Sponsors
Harvard University
National Center for Research Resources (NCRR)
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Pre-assignment details
Whether subjects received the solid or liquid preparation initially was randomly chosen.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants All study participants received a 15mg/kg dose of a solid acetaminophen formulation and a 15mg/kg dose of a liquid acetaminophen formulation separated by at least a 2 week washout period. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 6 | 0 / 9 |
| serious Total, serious adverse events | 0 / 6 | 0 / 9 |
Outcome results
Primary
Acetaminophen Metabolites
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.
Time frame: 8 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acetaminophen Solid Formulation | Acetaminophen Metabolites | 2.411 mcg.hr/ml | Standard Error 0.21 |
| Acetaminophen Liquid Formulation | Acetaminophen Metabolites | 2.009 mcg.hr/ml | Standard Error 0.17 |