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Codeine toxicokinetics in rats during a two-year dosed feed study

J Yuan, J K Dunnick, E R Barnes

    Drug Metabolism and Disposition: the Biological Fate of Chemicals
    |January 1, 1994
    PubMed
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    Codeine toxicokinetics in rats showed that plasma levels of codeine and morphine decreased over time, then increased at 24 months. Demethylation to morphine is the primary metabolic pathway in rats.

    Area of Science:

    • Pharmacology and Toxicology
    • Animal Studies
    • Drug Metabolism

    Background:

    • Understanding drug toxicokinetics is crucial for safety assessments.
    • Codeine is metabolized to morphine, a more potent analgesic.
    • Chronic exposure studies inform long-term safety profiles.

    Purpose of the Study:

    • To determine codeine toxicokinetics in rats over a 2-year period.
    • To investigate the impact of chronic codeine exposure via dosed feed.
    • To identify the primary metabolic pathways of codeine in rats.

    Main Methods:

    • F344 rats of both sexes received codeine in feed (0-1600 ppm) for 2 years.
    • Blood samples collected at multiple time points (days 7, 21, 90, 16 months, 24 months).
    • Plasma codeine and morphine concentrations measured by radioimmunoassay; conjugates determined after beta-glucuronidase treatment.

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    Main Results:

    • Plasma concentrations of codeine and morphine decreased from day 7 to 16 months, then increased at 24 months.
    • Codeine bioavailability via dosed feed ranged from 10-25%, dose-dependent and higher than gavage.
    • High concentrations of conjugated morphine and low conjugated codeine indicate demethylation is the main pathway.

    Conclusions:

    • Codeine metabolism to morphine is the primary pathway in rats and is sustained throughout chronic exposure.
    • Plasma drug concentrations correlate with feed concentrations, suggesting predictable exposure.
    • A late-phase increase in plasma concentrations at 24 months warrants further investigation.