Factors affecting the hepatic elimination of oxidized and of glucoronidated high clearance drugs following acute administration of carbon tetrachloride.
The factors affecting drug elimination following acute administration of carbon tetrachloride (CCl4) were investigated using a perfused rat liver system. Morphine and pethidine were used as markers of hepatic glucuronidation and oxidation, respectively. Hepatoxicity of CCl4 was indicated by widespread cellular necrosis and raised serum asparatate aminotransferase levels. At a perfusion rate of 10 ml/min, the extraction ratio of morphine in the normal liver was 0.67 +/- 0.18 and fell to 0.48 +/- 0.03 (p < 0.001) in the acutely damaged livers. The hepatic clearance of morphine fell from 6.7 +/- 0.2 ml/min in controls to 4.7 +/- 0.3 (p < 0.005) in the treated livers. Similar changes were seen at perfusion rates of 7 and 12 ml/min. Intrinsic clearances calculated according to both the venous equilibrium and the undistributed sinusoidal models were independent of perfusion rate and were also lower in the damaged livers. Perfusion rate was a dominant factor in determining morphine elimination in control livers. However, in the damaged livers, the fall in intrinsic clearance resulted in the elimination of morphine being mixed, i.e. both capacity and flow limited. At a perfusion rate of 10 ml/min, the extraction ratio of pethidine was 0.97 +/- 0.01 in control livers and was reduced to 0.91 +/- 0.02 (p < 0.005) in damaged livers. The hepatic clearance also fell at each perfusion rate in the damaged livers. As for morphine, the intrinsic clearances of pethidine calculated by both venous equilibrium and undistributed sinusoidal models gave qualitatively similar results and were lower in the damaged livers than controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Callaghan
R
R
Department of Clinical Pharmacology, St Vincent's Hospital, Fitzroy, Victoria, Australia.
Paull
P
P
Desmond
P V
PV
Mashford
M L
ML
D000208:Acute Disease; D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000150:complications / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008614:Meperidine / Q000378:metabolism; D008657:Metabolic Clearance Rate; D009020:Morphine / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D005965:Glucuronates; D009020:Morphine; D008614:Meperidine