The residence of morphine in the systemic circulation is prolonged des
pite a high systemic clearance, suggestive of significant extravascula
r sequestration. The present study was conducted to test the hypothesi
s that morphine binds significantly in tissues, and that the liver pla
ys an important role in morphine binding. [C-14]Morphine was administe
red to male Sprague-Dawley rats 55 min before unlabeled morphine or sa
line. Blood C-14 increased immediately after injection of unlabeled mo
rphine; the area under the blood concentration-time curve (AUG) for C-
14 increased similar to 2-fold after morphine compared with saline inj
ection. Residual radioactivity in the liver was lower in morphine-trea
ted rats than in controls, suggesting that unlabeled drug displaced [C
-14]morphine (or a metabolite) from binding sites. To examine this phe
nomenon more directly, a recirculating isolated perfused liver system
was employed. [C-14]Morphine was added to the perfusate reservoir 15 m
in before unlabeled morphine or saline; perfusate and bile samples wer
e collected for 120 min. Upon termination of perfusion, the liver was
fractionated to identify the hepatic subcellular fraction(s) in which
morphine was sequestered. The perfusate AUC for [C-14]morphine was inc
reased similar to 2-fold in response to unlabeled drug, consistent wit
h the in vivo experiment. Morphine was associated preferentially with
the cytosolic fraction, and [C-14]morphine in all relevant fractions w
as reduced after administration of unlabeled morphine. In contrast, un
labeled drug had no influence on derived [C-14]morphine-3-beta,D-glucu
ronide. These data are consistent with significant, reversible binding
of morphine in hepatic tissue.