Increased sensitivity of propranolol clearance to reduced oxygen delivery in the isolated perfused cirrhotic rat liver.
OBJECTIVE
Capillarization of the sinusoids in cirrhosis is proposed to reduce oxygen availability to the hepatocyte, resulting in the patterns of altered drug metabolism observed in cirrhosis. If this were true, drug metabolism in cirrhotic livers would be expected to be more sensitive to reduced oxygen delivery than in noncirrhotic livers. The aim of this study was to compare the sensitivity of propranolol clearance with reduced oxygen delivery in isolated perfused livers from healthy and cirrhotic rats.


METHODS
Propranolol clearance was measured at steady state in 5 normal and 5 cirrhotic weight-matched perfused rat livers under single-pass conditions with normal oxygen delivery (mean, 71.5 mumol/min) and with graded reductions in oxygen delivery (range, 58.1-18.8 mumol/min).


RESULTS
In noncirrhotic livers, propranolol clearance was independent of oxygen supply for the oxygen delivery range of 73-45 mumol/min but decreased with further reductions in oxygen supply. In cirrhotic livers, propranolol clearance decreased linearly (r2 = 0.92; P < 0.005) for the entire oxygen delivery range (73.4-18.8 mumol/min).


CONCLUSIONS
The increased sensitivity of propranolol clearance in perfused cirrhotic livers to reductions in oxygen delivery is consistent with impaired oxygen delivery to hepatocytes in cirrhosis. These novel findings potentially hold implications for clinical management of patients with cirrhosis.
Hickey
P L
PL
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Melbourne, Victoria, Australia.
McLean
A J
AJ
Angus
P W
PW
Choo
E F
EF
Morgan
D J
DJ
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D008099:Liver / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D010477:Perfusion; D011433:Propranolol / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity
D000319:Adrenergic beta-Antagonists; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D010100:Oxygen