CSF concentrations of morphine-6-glucuronide after oral administration of morphine

The role of locally situated effect of codeine inhibitory transit in man.

opioid receptors on gastrointestinal

in

the

Poster 75 BROWN Mon-Tue! ACC Hall E Abs No

selstm, C. Alm, *M. Eriksson and J. Sdwe, Depts. of Clinical Pharmacology and *Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden

382

Aim of investiaation: This study aimed at evaluate the reiative contribution of locally situated opioid receptors in the gut on orocecatransit time in 12 healthy volunteers. Methods: Single doses of codeine 50 mg was administered Orally and rectally in a double blind, double dummy, randomized fashion. After a standardized meal and 10 g of laculose the Hz-content in expired air was analyzed every 15th minute and from the Hz-content

versus time curve the

orocecal transit time was calculated. Results: A significantly longer orocecal transit time after the oral dose compared to the rectal was found. Relative bioavailability.or differences in metabolite formation could not explain the findings. Conclusion: A slowing in the gastrointestinal transit depending on rhe route of administration has been found. This suggests that the locall.!: situated opioid receptors might mediate gastrointestinal effects additive to those of the central nervous system. Thus in the clinical situation where such side effects are present the rectal route might be an alternative to parentera routes.

CSF CONCENTRATIONSOF MORPHINE-6-GLUCURONIDE AFTER ORAL ADMINISTRATION OF MORPHIYE Poulain P *Moran Ribon A,'*, Hanks GW2 Hoskin PJ*,* Aherne GW3,* Chapman DP3,*. InstitutGustave Roussy', Rue Camille2Desmoulins, 94805 VillejuifCeder, France, Royal Marsden Hospital , London UK, and Universityof Surrey , Guildford,UK.

Poster 76 BROWN Mon-Tues ACC Hall E Abs No

383

1

AIM OF INVESTIGATION: It has been suggestedthat the metabolitemorphine-6-glucuronide (M6G) accounts for the major part of the pharmacodynamiceffects of repeated oral doses of morphine. This study investigatedthe time course of M6G concentrationsin CSF followingoral administrationof morphine. METHODS: A single dose of 2Cmg aqueous morphine sulphatewas given to two morphine-naive patientswith advanced cancer about to be treated with intrathecalmethotrexatevia an indwellingintrathecalcatheter. Serial venous blood and CSF samples were obtained and morphine and M6G were measured by means of a specific RIA and a differentialRIA technique. RESULTS: Peak concentrationsof unconjugatedmorphine were achieved in plasma at : hour and of M6G at 2 hours in both patients. In contrast peak concentrationsof morphine and M6G in CSF were achieved at 4 and 6 hours in patient 1, and at 8 hours in patient 2. Comparisonof the areas under the curve (AUC) of CSF concentrationversus time showed that the ratio of morphine to M6G was I:6 in patient 1 and l:2.4 in patient 2. Plasma AUC ratios of morphine to M6G were I:9 and 1:ll. CONCLUSIONS: These data demonstratethe presence of significantamounts of M6G in CSF after oral administrationof morphine to humans. Peak concentrationsare not achieved until several hours after dosing.