CODEINE TOXICOKINETICS IN RATS DURING A 2-YEAR DOSED FEED STUDY

Codeine toxicokinetics in F344 rats of both sexes were determined duri ng a 2-year chronic toxicology study using dosed feed as the exposure route with a 12 hr light/dark cycle starting at 7:00 a.m. Rats were al lowed to access to dosed feed formulations ad libitum with codeine con centrations at 0, 400, 800, and 1600 ppm. Blood samples were collected from individual rat on days 7, 21, and 90 at 7:00 p.m., 11:00 p.m., 3 :00 a.m., and 7:00 a.m. Additional samples were collected at 16 and 24 months between 6:00-8:00 a.m. Plasma concentrations of codeine and mo rphine were determined directly by radioimmunoassay. Concentrations of their conjugates were determined indirectly by measuring the total am ount of free codeine and morphine released after samples were treated with beta-glucuronidase. Results indicated that plasma concentrations of both codeine and morphine steadily decreased from day 7 to 16 month s and then rebounded at 24 months. Results also indicated that plasma concentrations of both codeine and morphine correlated well with the a mounts of codeine added to the feed. Bioavailability of codeine using the dosed feed route increased with dose, varying from 10% to 25%, whi ch was somewhat higher than the previously reported similar to 8% bioa vailability using the gavage route. Concentrations of conjugated codei ne were very low, whereas concentrations of conjugated morphine were v ery high. These results suggested that demethylation of codeine to mor phine in rats is the main metabolic pathway and was maintained over th e course of the study.