Ta. Aasmundstad et J. Morland, DIFFERENTIAL INHIBITION OF MORPHINE GLUCURONIDATION IN THE 3-POSITIONAND 6-POSITION BY RANITIDINE IN ISOLATED HEPATOCYTES FROM GUINEA-PIG, Pharmacology & toxicology, 82(6), 1998, pp. 272-279
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.