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 significant analgesic effects in animals and humans. To evaluate route‐specific differences in the potential contribution of morphine‐6‐glucuronide to morphine analgesia, we studied the pharmacokinetics of morphine, morphine‐6‐glucuronide, and morphine‐3‐glucuronide after oral and rectal administration of morphine sulfate in a six‐subject randomized, single‐dose, two‐way crossover evaluation. The mean area under the plasma concentration‐time curve (AUC) molar ratios of morphine‐6‐glucuronide (M6G) and morphine‐3‐glucuronide (M3G) to morphine (M) were greater after oral morphine administration compared with rectal morphine administration (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 plasma concentrations of morphine‐6‐glucuronide and morphine‐3‐glucuronide were significantly greater after oral morphine administration compared with the rectal route (AUC: M6G, 377.1 ± 124.2 versus 236.2 ± 133.7 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 versus 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 difference 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 of hepatic biotransformation, and they provide a convincing argument for the evaluation of morphine‐6‐glucuronide concentrations in pharmacokinetic and pharmacodynamic comparisons involving different routes of morphine administration. Clinical Pharmacology and Therapeutics (1993) 54, 286–292; doi: 10.1038/clpt.1993.149