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Research ArticleArticle

Absorption, Disposition Kinetics, and Metabolic Pathways of Cyclohexene Oxide in the Male Fischer 344 Rat and Female B6C3F1 Mouse

John-Michael Sauer, Jingqi Bao, Richard L. Smith, Thomas D. McClure, Michael Mayersohn, Usha Pillai, Michael L. Cunningham and I. Glenn Sipes
Drug Metabolism and Disposition March 1997, 25 (3) 371-378;
John-Michael Sauer
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Jingqi Bao
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Richard L. Smith
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Thomas D. McClure
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Michael Mayersohn
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Usha Pillai
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Michael L. Cunningham
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I. Glenn Sipes
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Abstract

Cyclohexene oxide (CHO) is a monomer intermediate used in the synthesis of pesticides, pharmaceuticals, and perfumes. Although CHO has a variety of industrial uses where direct human exposure is possible, very little is known about its fate in the body. Therefore, the objectives of this study were to determine the absorption, distribution, metabolism, and excretion of cyclohexene oxide after oral, intravenous, and dermal exposure in male Fischer 344 rats and female B6C3F1 mice. After intravenous administration of [14C]CHO (50 mg/kg), CHO was rapidly distributed, metabolized, and excreted into the urine. Plasma concentrations of CHO rapidly declined and were below the limit of detection within 60 min. Average (±SD) values for terminal disposition half-life, apparent volume of distribution at steady-state, and systemic body clearance were: 19.3 ± 1.6 min; 0.44 ± 0.08 liter/kg; and 31.3 ± 0.5 ml/kg * min, respectively. After oral administration of [14C]CHO (10 and 100 mg/kg), it was found that14C-equivalents were rapidly excreted in the urine of both species. At 48 hr, the majority of the dose (73–93%) was recovered in urine, whereas fecal elimination accounted for only 2–5% of the dose. At no time after oral administration was parent CHO detected in the blood. However, its primary metabolite cyclohexane-1,2-diol was present for different lengths of time depending on the dose. Four metabolites were detected and identified in mouse urine by MS: cyclohexane-1,2-diol; cyclohexane-1,2-diol-O-glucuronide;N-acetyl-S-(2-hydroxycyclohexyl)-l-cysteine; and cyclohexane-1,2-diol-O-sulfate. The sulfate conjugate was not present in rat urine. Topical application of [14C]CHO (60 mg/kg) provided poor absorption in both species. The majority of 14C-equivalents applied dermally were recovered from the charcoal skin trap (∼90% of the dose). Only 4% of the dose was absorbed, and the major route of elimination wasvia the urine. To evaluate the toxicity of CHO, animals were given daily doses of CHO orally and topically for 28 days. No statistically significant changes in final body weights or relative organ weights were noted in rats or mice treated orally with CHO up to 100 mg/kg or up to 60 mg/kg when given topically. Very few lesions were found at necropsy, and none were considered compound related. In conclusion, regardless of route, CHO is rapidly eliminated and excreted into the urine. Furthermore, after either oral or dermal administration, it is unlikely that CHO reaches the systemic circulation intact due to its rapid metabolism, and is therefore unable to cause toxicity in the whole animal under the test conditions used in this study.

Footnotes

  • Send reprint requests to: Dr. I. Glenn Sipes, Department of Pharmacology and Toxicology, College of Pharmacy, P.O. Box 210207, The University of Arizona, Tucson, AZ 85721-0207.

  • ↵1 Present address: Chemical Branch, National Institute of Environmental Health.

  • This research was supported by a contract from NIEHS (ES-35367) and the NIEHS-sponsored Southwest Environmental Health Sciences Center (P30-ES-06694). J-.M.S. was supported in part by a Graduate Training Program in Environmental Toxicology Fellowship (T32-ES-07091-17).

  • Abbreviations used are::
    CHO
    cyclohexene oxide
    GSH
    glutathione
    FID
    flame ionization detector
    JVC F-344
    Fischer 344 rats with jugular vein cannula
    CLs
    systemic clearance
    Vss
    steady-state volume of distribution
    t½
    terminal disposition half-life
    MRT
    mean residence time
    AUC
    area under the curve
    AUMC
    area under the first moment of the plasma concentration-time curve
    CID
    collision-induced dissociation
    EI
    electron ionization
    CHOX
    cyclohexanone oxime
    NIEHS
    National Institute of Environmental Health Sciences
    • Received September 13, 1996.
    • Accepted November 26, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 3
1 Mar 1997
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Research ArticleArticle

Absorption, Disposition Kinetics, and Metabolic Pathways of Cyclohexene Oxide in the Male Fischer 344 Rat and Female B6C3F1 Mouse

John-Michael Sauer, Jingqi Bao, Richard L. Smith, Thomas D. McClure, Michael Mayersohn, Usha Pillai, Michael L. Cunningham and I. Glenn Sipes
Drug Metabolism and Disposition March 1, 1997, 25 (3) 371-378;

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Research ArticleArticle

Absorption, Disposition Kinetics, and Metabolic Pathways of Cyclohexene Oxide in the Male Fischer 344 Rat and Female B6C3F1 Mouse

John-Michael Sauer, Jingqi Bao, Richard L. Smith, Thomas D. McClure, Michael Mayersohn, Usha Pillai, Michael L. Cunningham and I. Glenn Sipes
Drug Metabolism and Disposition March 1, 1997, 25 (3) 371-378;
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