An extended physiological pharmacokinetic model of methadone disposition in the rat: validation and sensitivity analysis.

An extended physiological model of methadone disposition in the rat was constructed and evaluated in various tests of model validity. A separate circulation model of the fetus was included due to the large tissue concentration differences obtained after a constant rate infusion but also to propose the use of this type of model for optimization of toxicological tests. Simulations were performed with the animal model and scaled-up models of humans to elucidate the determinants of methadone disposition. The rationale of the use of an extended model for methadone was also discussed.