Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing

Condition(s) targeted: Acetaminophen Toxicity

Intervention: Acetaminophen (Drug); Acetaminophen/Propelyne Glycol (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Beth Israel Deaconess Medical Center

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

Overall contact:
Steven Salhanick, MD, Phone: 617-754-2323, Email: ssalhani@bidmc.harvard.edu

A purpose of this protocol is to is to compare the metabolites of the toxic bioactivating pathway after acetaminophen alone or acetaminophen followed by Propylene Glycol (PG) and to determine if it prevents the formation of the toxic metabolites of acetaminophen.

Official title: Protective Effects of Propylene Glycol in Daily Acetaminophen Dosing

Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Prevention

Primary outcome: Inhibition of rise in plasma transaminases

Detailed description: The purpose of this protocol is to contribute to our overarching purpose, which is to determine if inhibiting the bioactivation of acetaminophen (APAP) can prevent liver injury, and to further describe the initiating mechanisms of APAP induced liver injury. APAP induced liver injury is caused by metabolism and/or the resulting metabolites when APAP undergoes reductive metabolism via the cytochrome P450 (CYP) system, principally via CYP 2E1. Inhibition of CYP 2E1 activity protects against toxicity in rodents and tissue culture 1, 2. Our prior research indicates that inhibition of CYP 2E1 by administering a pediatric preparation of APAP containing Propylene Glycol (PG), a known CYP 2E1 inhibitor, results in reduced production of CYP 2E1 derived metabolites via competitive inhibition. In this proposed protocol the investigators will provide therapeutic doses of APAP and a separately administered non toxic dose of PG over a two-week period to healthy subjects. 20-75% of healthy people who take therapeutic doses of APAP for 7-28 days will have an asymptomatic and subclinical rise in transaminase levels that will return to baseline without adverse effect or therapy. 3 The return to baseline occurs despite continued dosing of APAP (heard review 9 and 17). A primary purpose is to determine if PG is, in fact, the substance in the liquid preparation responsible for the effect the investigators observed in the investigators initial study. A secondary purpose is to obtain plasma samples for secondary metabolomic analysis to elucidate the effect of CYP 2E1 inhibition. Specific Aims

- 1 To demonstrate that co-administration of PG with APAP prevents the rise in AST/ALT

expected in approximately one third of subjects following therapeutic dosing of APAP over days.

- 2 To show that PG administered with APAP reduces toxic P450-derived metabolite

production following therapeutic APAP administration.

- 3 To obtain plasma samples to undergo metabolomic and other analyses to determine the

effects of CYP 2E1 inhibition in the setting of APAP administration.

- 4: To undergo metabolomic analyses on the day LFT's peak to determine differences in

metabolomics parameters between subjects receiving propylene glycol plus acetaminophen versus just acetaminophen alone.

Minimum age: 20 Years. Maximum age: 40 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Healthy volunteers ages 20-40

- Patients not taking any chronic medications

Exclusion Criteria:

- Any history of liver disease

- Frequent alcohol use (2 or more drinks more than 4 times per week)

- Pregnant women

- Chronic medical condition requiring daily pharmacotherapy or the use of any daily

prescription medications.

- Unable to provide informed consent

Steven Salhanick, MD, Phone: 617-754-2323, Email: ssalhani@bidmc.harvard.edu

Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, United States; Recruiting
Steven Salhanick, MD, Phone: 617-754-2323, Email: sslanhani@bidmc.harvard.edu

Starting date: May 2013
Last updated: December 22, 2014