Pharmacokinetics of morphine in cancer patients following multiple administrations of controlled-release morphine tablet (MS contin).

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MS Contin tablet is a newly formulated controlled-release morphine sulfate tablet. It has the advantage of less frequence of dosing over conventional dosage forms because of the long-lasting effective plasma concentration. In this study, pharmacokinetics of morphine and its metabolites (M-6-G, morphine-6-glucuronide ; M-3-G, morphine-3-glucuronide) were studied in patients with advanced cancer, following multiple administrations of MS Contin. Morphine was well absorbed from MS Contin tablet, comparably with aqueous morphine hydrochloride. The plasma concentrations of M-6-G and M-3-G were 5- to 10-fold and 40- to 70-fold higher, respectively, than those of morphine, indicating that morphine is substantially metabolized at the first pass through the intestine and liver. The elimination half-lives of morphine and its metabolites were constant during multiple dosing, but the ratios of Cmax and AUC of morphine at steady state to those after the first dose were greater than the calculated accumulation factor. On the other hand, the ratios of Cmax of M-6-G and M-3-G were comparable with the accumulation factor. The nonlinearity observed for morphine and the linearity found for the two metabolites during multiple doses may be explained by the very small reduction of first-pass metabolism which is thought to be caused by advances of cancer.
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