Objective: This investigation focused on the development of a predictive model of morphine, including morphine-6-glucuronide (M6G) for healthy young volunteers after morphine administration.
Methods: Population compartmental pharmacokinetic modeling with NONMEM was applied to the plasma concentration-time data of morphine and M6G obtained from 8 healthy volunteers (4 men and 4 women; age range, 23 to 30 years) after intravenous bolus injection of 5.64 mg morphine base (7.5 mg morphine sulfate) and of 1 mg deuterium-labeled M6G.
Results: Two models were identified that described the plasma concentration versus time courses of morphine and M6G after administration of morphine. The model consisted of a standard 3-compartment model for morphine and a standard 2-compartment model for M6G, with input into and output from the central compartments. The formation of M6G from morphine was modeled as a fraction of morphine clearance of about 14%, which accounted for the formation of M6G, and a delay of the appearance of M6G in plasma modeled as a first-order process, with a mean metabolic transit time of 17.2 minutes. An alternative model assigned the formation of M6G among the first peripheral compartment of morphine and the central compartment of M6G. Therefore the alternative 3-compartment model of morphine had the input into the central compartment and renal excretory elimination from the central compartment, but the metabolic clearance of morphine started from the first peripheral compartment. M6G was again modeled with a standard 2-compartment model. Both models predicted morphine and M6G plasma concentrations available from an independent study with acceptable accuracy and without bias.
Conclusions: Two models are provided that can predict plasma concentrations of morphine and M6G with acceptable accuracy in healthy young volunteers.