Evidence for saturable incorporation of methadone into rat hair: relationships among oral dose, plasma concentration, and hair content.

Six groups of six male Wistar rats were administered methadone in their drinking water over the concentration range 0-0.25 mg/ml. Hair and trunk blood samples were collected after a 6-week period of drug administration. Immunoreactive methadone was measured by radioimmunoassay and methadone and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP), by gas chromatography in plasma and alkali digests of hair. Plasma methadone concentration increased with increasing oral dose. The mean hair concentration of methadone increased to a maximum of 5.1 ng/mg at a drinking water concentration of 0.1 mg/ml corresponding to a plasma level of 14.0 ng/ml. No further significant rise in hair content was seen with higher drinking water concentrations despite a continuing increase in oral drug intake and in plasma methadone concentration. EDDP was not detected in plasma but was present at > 2 ng/mg in 25% of hair samples. The mean EDDP concentration in hair peaked at 3.2 ng/mg at the lowest dose level of methadone administered. The data suggest that methadone is incorporated into rat hair via a capacity-limited process that becomes saturated at plasma levels of some 14 ng/ml. Competition for uptake into hair between methadone and EDDP may occur.