The Pharmacokinetics of Hexachlorobenzene in Male Beagles

Sundlof, Stephen Frederick

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Description

Title

The Pharmacokinetics of Hexachlorobenzene in Male Beagles

Author(s)

Sundlof, Stephen Frederick

Issue Date

1980

Department of Study

Veterinary Medical Science

Discipline

Veterinary Medical Science

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Health Sciences, Pharmacology

Language

eng

Abstract

• The distribution, metabolism, and excretion of hexachlorobenzene were studied in male Beagle dogs. Distribution of HCB was determined in animals following single intravenous and multiple oral administrations in HCB. Metabolism and excretion of HCB were studied following single intravenous administrations of ('14)C-labeled HCB. Detection and quantitation of HCB was accomplished using electron-capture, gas-liquid chromatography while detection and quantitation of ('14)C was carried out using liquid scintillation spectrometry.
• Early distribution of HCB following a single I.V. administration of HCB dissolved in olive oil resulted in a large percentage of the dose being trapped in the lungs. This was determined to be the result of microemboli formation by the oily injection vehicle which lodged in the capillary beds of the lungs. From the lungs, HCB rapidly distributed to highly perfused tissues. Disappearance of HCB from these tissues occurred rapidly between 2 and 8 hours following administration of the dose, but between 8 and 48 hours the decline in tissue concentrations occurred at a gradual rate. This biphasic decay in tissue HCB concentrations paralleled the disappearance of HCB from blood. Adipose tissue was the only tissue to accumulate HCB between 2 and 8 hours following administration of the dose. The concentration of HCB in adipose greatly exceeded the concentrations found in most other tissues.
• The distribution of HCB in Beagles receiving daily oral administrations of 10 or 100 mg per kg body weight HCB for seven consecutive days also greatly favored tissues containing high fat content. These tissues included adipose tissue, bone marrow, and skin. Evidence was found indicating that absorption of HCB crystals from the intestinal tract continued for several days following the cessation of dosing. Also, absorption efficiency was determined to be reduced at the higher dose level.
• The presence of metabolites of HCB could not be demonstrated in the blood or tissues of Beagles receiving a single I.V. administration of ('14)C-HCB. However, it was determined that 100 percent of urine radioactivity and greater than 60 percent of fecal radioactivity occurred as metabolites. Approximately 96 percent of the total radioactivity excreted in the bile was determined to be metabolites.
• Studies conducted to examine the excretion of HCB and HCB metabolites through urinary and fecal routes revealed that fecal excretion was the major pathway for the overall excretion of the dose. Fecal excretion was determined to be composed of two distinct excretory processes, biliary excretion and excretion of parent HCB through the intestinal tract proper. Of these two processes, biliary excretion was determined to be the major contributor to fecal excretion. The dog appears to be the only species studied to date in which excretion of metabolites rather than parent compound is primarily responsible for reduction of the total body burden of HCB.
• Pharmacokinetic analysis of blood, urine, and fecal radioactivity data resulted in the construction of 2 and 3 compartment models for 3 animals receiving a single I.V. administration of ('14)C-HCB. The models accurately described the observed blood concentration data, and a direct proportionality was determined to exist between the concentration of ('14)C in the blood and the amount excreted in the urine and feces. Half-life values ranging between 35 and 54 days were derived from blood disappearance curves; however, the necessary addition of an extraneous rate constant, k(,undefined), falsely decreased the half-life values in two animals.
• By comparing the mathematical models to the experimental data generated from the distribution studies, it was concluded that the central compartment included the major body organs while the peripheral compartments were composed primarily of adipose tissue.

Graduation Semester

1980

Type of Resource

text

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