A new mode of action of SKD 525-A on morphine disposition studied by segmented retrograde intrabiliary injection (SRII) in the isolated in situ perfused rat liver.
The effect of SKF-525-A on the disposition of morphine given by segmented retrograde intrability injection (SRII) was studied in the isolated in situ perfused livers of Sprague-Dawley male rats. SRII of morphine repeated after treatment SKF 525-A (20 mg/kg b. wt. intraportally) showed decreased recovery of morphine glucuronide (MG) in the bile and in the venous outflow. On the other hand, morphine in the venous outflow was increased. Thus, SKF 525-A decreased the total recovery (bile plus venous outflow) of MG. The results after intraportal administration of morphine were consistent with these observations by SRII. These results might indicate inhibition of conjugation by SKF 525-A. However, a similar effect of SKF 525-A was obtained when MG was given by either route. These latter results were interpreted to mean tht SKF 252-A affected a translocation process for MG. Analysis of the liver after the SRII of MG indicated that SKF 525-A caused a 10-fold increase in retention of MG in the liver. Based on the cumulative venous outflow curves, the difference in apparent volumes of distribution, Q, indicated that morphine was taken up by hepatocytes beyond the mannitol, total liver water (intra- and extracellular) space and SKF 525-A decreased this apparent volume of distribution of morphine. Also, SKF 525-A increased the apparent volume of distribution of MG. The mean transit time of morphine was not altered by SKF 525-A whereas that of MG became longer. The evidence indicated that SKF 525-A decreased the egress of MG from liver, a newly recognized mode of action of SKF 525-A.
D000818:Animals; D001646:Bile / Q000032:analysis*; D005965:Glucuronates / Q000097:blood* / Q000494:pharmacology; D007267:Injections; D008099:Liver / Q000378:metabolism*; D008111:Liver Function Tests; D008297:Male; D009020:Morphine / Q000378:metabolism* / Q000494:pharmacology; D010477:Perfusion; D011335:Proadifen / Q000494:pharmacology*; D051381:Rats
D005965:Glucuronates; D009020:Morphine; D011335:Proadifen