DISPOSITION OF MORPHINE AND ITS GLUCURONIDE METABOLITES AFTER ORAL AND RECTAL ADMINISTRATION - EVIDENCE OF ROUTE SPECIFICITY

Morphine-6-glucuronide is a metabolite of morphine that shows signific ant analgesic effects in animals and humans. To evaluate route-specifi c differences in the potential contribution of morphine-6-glucuronide to morphine analgesia, we studied the pharmacokinetics of morphine, mo rphine-6-glucuronide, and morphine-3-glucuronide after oral and rectal administration of morphine sulfate in a six-subject randomized, singl e-dose, two-way crossover evaluation. The mean area under the plasma c oncentration-time curve (AUC) molar ratios of morphine-6-glucuronide ( M6G) and morphine-3-glucuronide (M3G) to morphine (M) were greater aft er oral morphine administration compared with rectal morphine administ ration (M6G/M ratio, 2.7: 1 versus 1.3: 1, p = 0.025; M3G/M ratio, 18. 3: 1 versus 9.3: 1, p = 0.002). Systemic bioavailability and peak plas ma concentrations of morphine-6-glucuronide and morphine-3-glucuronide were significantly greater after oral morphine administration compare d with the rectal route (AUC: M6G, 377.1 +/- 124.2 versus 236.2 +/- 13 3.7 nmol . hr/L, p = 0.05; M3G, 2610.1 +/-446.4 versus 1650.2 +/- 309. 0 nmol . hr/L, p = 0.004; maximum concentration: M6G, 110.9 +/- 37.5 v ersus 64.6 +/- 28.8 nmol/L, p = 0.002; M3G, 576.9 +/- 155.8 versus 266 .8 +/- 110.5 nmol/L, p = 0.007). Conversely, the systemic availability of morphine was lower after oral administration, although this differ ence failed to achieve statistical significance (142.3 +/- 17.1 versus 176.6 +/- 69.4 nmol . hr/L, p = 0.14). These data suggest that rectal administration of morphine is associated with significant avoidance o f hepatic biotransformation, and they provide a convincing argument fo r the evaluation of morphine-6-glucuronide concentrations in pharmacok inetic and pharmacodynamic comparisons involving different routes of m orphine administration.