Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers

Background: Morphine is metabolized to two major metabolites, morphine-3-gl ucuronide and morphine-G-glucuronide (M6G). Under the conditions of long-te rm oral morphine administration, the accumulation of M6G may contribute to the analgesic effects, but it may also cause respiratory depression. Methods: Five healthy male volunteers (ages 25-34 yr) received 90 mg MST (m orphine sulfate 5H(2)O sustained-released tablet, equivalent to 67.8 mg ora l morphine). Multiple plasma and urine samples were taken for as long as 14 and 36 h, respectively. Individual pharmacokinetics after intravenous admi nistration of morphine and M6G were available from a previous investigation . A new model that considers the M6G-plasma profile as a sum of the input f rom the first-pass metabolism of morphine and the input from systemically a vailable morphine was applied to the plasma concentration versus time curve s of M6G, The concentrations of M6G at the effect site after long-term morp hine administration were simulated, Results: The fraction of morphine absorbed from the gut was 82 +/- 14%. Of this, 42 +/- 8% passed through the Liver, resulting in an oral bioavailabil ity of morphine of 34 +/- 9%. Of the total amount of M6G, 71 +/- 7% was for med during the first-pass metabolism, and 29 +/- 7% was formed by metabolis m of systemic morphine. After 36 h, the amounts of M6G and morphine excrete d in the urine were 92 +/- 17% and 9 +/- 3%, respectively. Simulation of ef fect-site concentrations of M6G indicated that after multiple oral dosing o f morphine in patients with normal liver and renal function, M6G might reac h concentrations two times greater than that of morphine. Conclusions: M6G may contribute to the analgesic and side effects seen with long-term morphine treatment. The current model of morphine and M6G pharma cokinetics after oral administration of morphine may serve as a pharmacokin etic basis for experiments evaluating the analgesic contribution of M6G wit h long-term oral dosing of morphine.