Pharmacokinetics of morphine-6-glucuronide and its formation from morphine after intravenous administration*

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Abstract
Background Morphine‐6‐β‐glucuronide is a primary morphine metabolite with potent opioid action. However, its low and slow brain permeability eventually prevents its central opioid effects after short‐term intravenous administration. Research is needed to establish whether morphine‐6‐β‐glucuronide qualifies as an analgesic; this study provides the pharmacokinetic bases for such studies. Methods Plasma concentration‐time data of morphine‐6‐β‐glucuronide and morphine obtained from 20 healthy volunteers after short‐term intravenous administration of either morphine‐6‐β‐glucuronide or morphine were described by a biexponential disposition curve. Disposition parameters of morphine‐6‐β‐glucuronide and morphine were estimated by nonlinear regression, and basic pharmacokinetic parameters (clearance, volume of distribution at steady state, and mean disposition residence time) were derived. A new model of metabolite kinetics was applied, and the disposition parameters of morphine and morphine‐6‐β‐glucuronide were then used to fit the plasma concentration‐time profile of morphine‐6‐β‐glucuronide formed from morphine. Thereby the fraction of morphine metabolized to morphine‐6β‐glucuronide and the mean transit time of morphine across the site of metabolism were estimated. Results The extent and time course of morphine‐6‐β‐glucuronide formation from morphine could be well described by a parametric model, with a fraction of morphine metabolized to morphine‐6‐β‐glucuronide of 7.55% ± 1.24% and a mean metabolic transit time for morphine to morphine‐6‐β‐glucuronide of 0.28 ± 0.21 hour. The underlying disposition of morphine and morphine‐6‐β‐glucuronide was characterized by clearance (morphine clearance, 32.7 ± 6 ml · min−1 · kg−1, morphine‐6‐β‐glucuronide clearance, 2.2 ± 0.4 ml · min−1 · kg−1), volume of distribution at steady state (morphine, 1.8 ± 0.3 L · hr−1; morphine‐6‐β‐glucuronide, 0.12 ± 0.02 L · hr−1), and mean disposition residence time (morphine, 1.8 ± 0.4 hours; morphine‐6‐β‐glucuronide, 1.7 ± 0.4 hours). Conclusions The time course of morphine‐6‐β‐glucuronide formation kinetics was analyzed with use of the information on the disposition kinetics of both morphine and preformed morphine‐6‐β‐glucuronide, which was obtained by separate data fits. The transformation of morphine to morphine‐6‐β‐glucuronide could be described by two parameters characterizing the extent and delay of metabolite formation. The results of this study will serve as pharmacokinetic bases of future investigations of morphine‐6‐β‐glucuronide in human beings. Clinical Pharmacology & Therapeutics (1998) 63, 629–639; doi: