Morphine and metabolite behavior after different routes of morphine administration: Demonstration of the importance of the active metabolite morphine‐6‐glucuronide

The pharmacokinetic parameters of morphine, morphine‐6‐glucuronide, and morphine‐3‐glucuronide were studied after single‐dose morphine administration by five different routes. The quantitative significance of the active metabolite morphine‐6‐glucuronide was assessed, and the effects of novel dosing forms on morphine metabolism and distribution were examined. After administration of intravenous morphine the morphine‐6‐glucuronide plasma AUC exceeded that of morphine. After administration of oral morphine very low morphine levels were observed—the morphine‐6‐glucuronide plasma AUC exceeded that of morphine by a factor of 9:1. Sublingual, buccal, and sustained‐release buccal morphine tablet administration resulted in delayed absorption, with attenuation and delay of peak morphine and metabolite levels. Morphine bioavailability and morphine glucuronide production were not altered.