Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet

Environmental Exposure Clinical Trial

Official title:

Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03802721
• Other study ID #: LPI-8789
• Secondary ID: R01ES028600
• Status: Completed
• Phase: Early Phase 1
• Start date: January 24, 2019
• Est. completion date: February 1, 2024

Study information

• Verified date: February 2024
• Source: Oregon State University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Evaluation of the pharmacokinetics for [14C]-benzo[a]pyrene ([14C]-BaP) and metabolites in plasma and urine over 48 hours following a 50 ng dose (5.4 nCi) alone, following 7 days' consumption of Brussels sprouts, and following 7 days' consumption of a supplement containing 3,3'-diindolylmethane (DIM).

Description:

The pharmacokinetics for [14C]-BaP and metabolites will be assessed by UHLPC-Accelerator Mass Spectrometry (AMS, Lawrence Livermore National Laboratory) in plasma and urine collected over 48 hours following oral doses of 50 ng dose (5.4 nCi) alone, following 7 days' consumption of Brussels sprouts, and following 7 days' consumption of a supplement containing 3,3'-diindolylmethane (DIM).

The investigators hypothesize that pre-administration of Brussels sprouts or DIM will alter [14C]-BaP metabolism and increase the rate of elimination consistent with predictions based on a previously developed Physiologically-Based Pharmacokinetic (PBPK) model for BaP. Briefly, this hypothesis will be tested by dosing individuals with 50 ng [14C]-BaP alone and, following a 3-week washout period, ingestion of about 50 g Brussels sprouts or 300 mg of 3,3'-diindolylmethane (DIM) supplement for 7 days prior to the [14C]-BaP micro-dose. The impact of the supplement and the whole food will be assessed with respect to alterations in uptake from the GI tract, metabolism and rate of elimination. The consumption of cruciferous vegetables will be assessed at the beginning of the study by completion of a dietary questionnaire to examine typical eating patterns in the previous 3 months and by collection and extraction of blood and urine to assay for DIM by LC/ESI-MS/MS-SRM). In addition, for each phase, urine will be assayed for DIM as an estimate of crucifer or DIM supplement intake.

In preclinical and clinical studies, administration of Brussels sprouts or DIM impacts the activity of the same enzymes responsible for the phase 1 (CYP1A1 and CYP1B1) and phase 2 enzymes (GSTM1, UGT, SULT). Monitoring changes in β-estradiol metabolites will confirm the mechanism of alteration in the metabolic profile of [14C]-BaP.

Metabolite profiles and kinetics of elimination are predicted to be consistent with a BaP physiologically based pharmacokinetic (PBPK) model developed by Pacific Northwest National Laboratory (PNNL). A non-smoker, not exposed occupationally, receives 270-700 ng of BaP daily; about 95% dietary. The WHO has set an estimated safe daily lifetime (70 year/70 Kg individual, cancer endpoint) exposure to BaP of 42-350 ng. This protocol represents de minimus risk.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7
• Est. completion date: February 1, 2024
• Est. primary completion date: January 1, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 65 Years

Eligibility

Inclusion Criteria:

• Age 21-65 (inclusive)

• If female, must be post-menopausal or have had surgical sterilization to eliminate any possibility for fetal exposure

• Willing to defer blood donation for one month before, throughout, and one month after completion of study activities

• Willing to avoid consuming cruciferous vegetables, I3C or DIM supplements, smoked or cured meat or cheeses, or charcoal-grilled meats for 2 weeks prior to and during each study cycle (gas grilled foods acceptable)

• Health history review and physical assessment showing general good health, as determined by study physician. Acceptable physical exam may have been conducted as part of protocol 8233 or 8554 if subject has not had significant changes in health status.

Exclusion Criteria:

• Smoker (tobacco or other substances) or use of smokeless tobacco in past 3 months or living with smoker

• Regular use of medications that affect gut motility or nutrient absorption (e.g. cholestyramine, sucralfate, orlistat, pro- or anti-motility agents)

• History of gastrointestinal surgery (e.g. bariatric surgery, cholecystectomy) or gastrointestinal disorder (Crohn's disease, celiac disease, IBS, or colitis)

• Current or history of kidney or liver disease

• Prior high-dose 14C exposure from medical tests. (micro-dose 14C exposure not exclusionary)

• Occupational PAH exposure (e.g. roofers, asphalt pavers, fire-fighters, etc.)

• Regular use of indole-3-carbinol or DIM dietary supplements

• Allergy or intolerance to Brussels sprouts or similar foods

Related Conditions & MeSH terms

• Environmental Exposure

Intervention

Drug:
• [14C]-benzo[a]pyrene
Oral micro-dose (50 ng) (5.4 nCi)
• Brussels sprouts before 50 ng dose
Brussels sprouts for 7 days before 50 ng (5.4 nCi) dose of BaP
• DIM supplement before 50 ng dose
DIM supplement for 7 days before 50 ng (5.4 nCi) dose of BaP and coadministration with DIM supplement

Locations

Country	Name	City	State
United States	Oregon State University	Corvallis	Oregon

Sponsors (4)

Lead Sponsor	Collaborator
Oregon State University	Lawrence Livermore National Laboratory, National Institute of Environmental Health Sciences (NIEHS), Pacific Northwest National Laboratory

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma and urine 14C-BaP and 14C-BaP metabolite levels after oral dose	Plasma and urine levels of 14C-BaP and 14C-BaP metabolites measured by accelerator mass spectrometry	48 hours
Secondary	Peak plasma concentration of 14C-BaP Cmax	Determination of highest concentration of 14C-BaP in plasma	48 hours
Secondary	Time at highest plasma concentration of 14C-BaP Tmax	Determination of time at which plasma concentration of 14C-BaP is highest	48 hours
Secondary	Area under plasma concentration of 14C-BaP versus time curve AUC	Integration of concentration of 14C-BaP in plasma over time	48 hours
Secondary	Rate of elimination of 14C-BaP	Determination of constants for rate of elimination of 14C-BaP from plasma	48 hours
Secondary	Metabolites of 14C-BaP in plasma	Determination of plasma metabolites of 14C-BaP	48 hours
Secondary	Metabolites of 14C-BaP in urine	Determination of urinary metabolites of 14C-BaP	48 hours
Secondary	Metabolites of B-estradiol in urine	Determination of urinary metabolites of B-estradiol	-7 days and 48 hours
Secondary	Metabolites of B-estradiol in plasma	Determination of plasma metabolites of B-estradiol	-7 days and 48 hours
Secondary	Metabolites of DIM in plasma	Determination of plasma metabolites of DIM	-7 days and 48 hours
Secondary	Metabolites of DIM in urine	Determination of urinary metabolites of DIM	-7 days and 48 hours