DIFFERENTIAL INHIBITION OF MORPHINE GLUCURONIDATION IN THE 3-POSITIONAND 6-POSITION BY RANITIDINE IN ISOLATED HEPATOCYTES FROM GUINEA-PIG

The influence of ranitidine on morphine metabolism, with special empha sise on the ratio between morphine-3-glucuronide and morphine-6-glucur onide was studied in isolated guinea pig hepatocytes. Ranitidine reduc ed the K-el of morphine dose-dependently with a maximum effect of 50%, and increased the relative concentration of morphine-6-glucuronide to morphine-3-glucuronide. These effects could be due to a direct or ind irect effect on the conjugation enzymes involved, or an effect on the transport of morphine or glucuronides across cell membranes. The latte r explanation was rejected on the basis of the observation that the ra tios between intra-and extracellular concentrations of morphine, morph ine-3-glucuronide and morphine-6-glucuronide were not influenced by ra nitidine. Increasing concentrations of ranitidine gradually decreased the morphine-3-glucuronide/morphine-6-glucuronide ratio by up to 21%. This could stem from interference of energy or co-substrate supply, or through direct effects on the different UDPGTases involved. The obser vation that the present effect on morphine glucuronidation was the opp osite of that observed when administering a known co-substrate (UDPGA) depletor, indicated that in all probability the effect of ranitidine was a direct inhibition on the uridine 5'-diphosphate glucuronyltransf erases involved, with a more pronounced effect for the isoenzymes resp onsible for the 3'-glucuronidation.