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

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.

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.