Species variation in the disposition of nalbuphine and its acetylsalicylate ester analogue.

1. The disposition of (-)17-(cyclobutylmethyl)-4,5 alpha-epoxymorphinan-3,6 alpha, 14-triol (Nalbuphine, Nubain) and its 3-acetylsalicylate ester has been studied in rat and dog to determine whether this analogue can improve the oral bioavailability of nalbuphine. 2. In dog, administration of the acetylsalicylate analogue increased nalbuphine bioavailability 5-fold to 16% and this correlated with an increase in analgesic activity. 3. The disposition of the analogue in rat was characterized by low oral bioavailability and a short plasma half-life. 4. Although nalbuphine acetylsalicylate was rapidly hydrolysed to nalbuphine in rat, nalbuphine bioavailability was not increased in this species. 5. Other studies have shown that these conflicting results are due to species differences in nalbuphine metabolism. Conjugation at the 3-hydroxyl position is the major metabolic pathway for nalbuphine in dog but not rat. Consequently, 3-hydroxyl esters are ineffective prodrugs for nalbuphine in rat and probably man.