Pharmacokinetics of morphine 3-esters after oral administration in rabbits.

Pharmacokinetics of three morphine 3-esters-3-(2,2-dimethylvaleroyl) morphine (A), 3-(2-phenylbenzoyl) morphine (B), and 3-(2,2-diphenylpropionyl) morphine (C) was characterized after single oral administration in rabbits. Blood was sampled up to 24 h and cerebro-spinal fluid (CSF) was collected with the last blood sample. The concentration of the morphine 3-esters, morphine, morphine 3-glucuronide and morphine 6-glucuronide were determined in plasma and CSF using HPLC UV-detection. The morphine 3-esters were suggested to be a subject to marked presystemic elimination, since, in comparison to the administration of the un-esterified morphine, relatively low concentrations of morphine and morphine glucuronides were detected in plasma. The rate of disposition of morphine was dependent on the hydrolytic stability of the esters. The mean (+/- S.E.) plasma half-life of morphine was 0.9 +/- 0.2 h, 2.5 +/- 0.6 h and 3.5 +/- 3.5 h after the administration of A, B and C, respectively, compared to 0.9 +/- 0.2 h as estimated after the administration of non-esterified morphine. An analgesic effect will be achieved, since morphine was detected in CSF even 24 h after the application of the ester pro-drugs. It is concluded that esterification at the 3-position may be adapted to obtain sustained plasma levels of morphine.