Prodrugs for improved oral nalbuphine bioavailability: inter-species differences in the disposition of nalbuphine and its acetylsalicylate and anthranilate esters

Two prodrugs of nalbuphine (1), the acetylsalicylate (2) and anthranilate (3) esters, were prepared with the objective of increasing oral nalbuphine bioavailability. Hydrolysis rates in rat, monkey, dog, and human plasma, human whole blood, and rat and dog liver and intestine homogenates were measured. Nalbuphine bioavailability after oral nalbuphine doses was determined, also in rats, monkeys, and dogs, and compared to a published value for man. There were large inter-species variations in prodrug hydrolysis rates and in oral nalbuphine bioavailability, and the dog bore closest resemblance to man. Oral nalbuphine bioavailability in dogs was increased 3–4-fold after administration of 2 and approximately 9-fold after administration of 3. Levels of conjugated nalbuphine in plasma were reduced. This demonstrates the utility of the prodrug approach to reducing first-pass nalbuphine metabolism.