COMPLICATIONS IN ESTIMATION OF HEPATIC BLOOD-FLOW INVIVO BY PHARMACOKINETIC PARAMETERS - AREA UNDER CURVE AFTER CONCOMITANT INTRAVENOUS AND INTRA-PERITONEAL (OR INTRAPORTAL) ADMINISTRATION OF ACETAMINOPHEN IN RAT

Abstract

Hepatic blood flow can be estimated from the area under the blood or plasma concentration time curve of a drug following an i.v. dose and either an oral or i.p. dose. The validity of the method depends on several factors which alter the area under the curve, that is, hemodynamic interactions due to the drug or its metabolites, the use of plasma concentration as opposed to blood concentration data, incomplete absorption on oral or i.p. administration, enterohepatic recycling of the drug or its metabolite, and the presence of extrahepatic metabolism. The validity of the method was tested in rats with tracer doses of acetaminophen. After the simultaneous administration of an i.v. dose of 14C-acetaminophen and an intraportal dose of 3H-acetaminophen to rats, the availability after the first-pass hepatic extraction of acetaminophen in rats was 0.56 .+-. 0.05. Hepatic blood flow estimated by the area under the curve for the respective routes of administration was 78.1 .+-. 16.1 ml/min per kg. However, after the simultaneous administration of an i.v. tracer dose of 14C-acetaminophen and an i.p. dose of 3H-acetaminophen, the apparent availabilities calculated from the areas under the curve were highly variable and tended to be greater (0.73 .+-. 0.11). Thus the estimates of the hepatic blood flow also tended to be higher (159 .+-. 65 ml/min per kg).