Changes in morphine pharmacokinetics in nervous and peripheral tissues following different schedules of administration.

The pharmacokinetics of morphine were studied in various tissues of rats subjected to a single dose treatment (SDT, 30 mg/kg), constant dose treatment (CDT, 30 mg/kg daily for 8 days) and increasing dose treatment (IDT, twice daily, raising from an initial dose 20 mg/kg to the final 300 mg/kg). After CDT the elimination of morphine was slow and the drug was present in tissues in detectable amounts for over 24 hr, the area under the curve (AUC) values in the central nervous system increased significantly as compared with SDT. After IDT the elimination of morphine was rapid and the AUC values were decreased several times; in most of the tissues no detectable amount of morphine was present 24 hr after the last dose. The data indicate that morphine pharmacokinetics change after chronic treatment and depend on dosage schedule and that plasma concentration of morphine may not reflect the drug level in tissues, particularly in the central nervous system.