Metabolism of acetaminophen and phenacetin by isolated rat hepatocytes. A system in which the spatial organization inherent in the liver is disrupted.
The kinetics of sulfation of 3H-acetaminophen (preformed metabolite) and 14C-acetaminophen (generated metabolite) during the parallel incubations of tracer concentrations of 3H-acetaminophen and 14C-phenacetin in (a) isolated rat hepatocytes and (b) rat 9000g supernatant fractions from liver and from isolated hepatocytes were compared to results obtained from rat liver perfusion studies (Pang and Gillette, J. Pharmacol. Exp. Ther. 207, 178-194, 1978; Pang and Terrell, J. Pharmacol. Exp. Ther. 216, 339-346, 1981). The isolated rat hepatocytes and the subcellular fractions represent in vitro systems whose metabolic activities are apparently homogeneous and contrast the in situ rat liver perfusion system where differential distribution of drug metabolizing activities exists within the rigid architecture of the intact organ. The ratio of sulfation (intrinsic clearance = 23.8 ml/min/liver) to O-deethylation (intrinsic clearance = 11.7 ml/min/liver) activities within these isolated hepatocytes (2.2-2.7) and subcellular fractions (3.72) were similar, but were reversed in the perfused liver preparation (0.2-0.5) depending on the model of hepatic drug clearance used for the calculation. Moreover, the sulfation to O-deethylation activity in the isolated rat hepatocyte system was independent of cell concentration (3.8 to 11 X 10(8) cells/ml) or the method of isolation of hepatocytes (by normal digestion or retrograde digestion). The reason for the reversal of lower O-deethylation activity in the subcellular and cellular systems remains unknown.(ABSTRACT TRUNCATED AT 250 WORDS)
Pang
K S
KS
Kong
P
P
Terrell
J A
JA
Billings
R E
RE
D000082:Acetaminophen / Q000378:metabolism*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D010615:Phenacetin / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism
D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D007770:L-Lactate Dehydrogenase; D010615:Phenacetin