LIVER PERFUSION TECHNIQUE USING INEXPENSIVE NON-BINDING MEDIUM FOR 1ST-PASS METABOLISM STUDIES OF DRUGS

A rat liver perfusion technique which employs an inexpensive nonbinding medium has been developed and evaluated for first-pass drug kinetic studies. The perfusate consisted of a modified Krebs-Henseleit solution containing sucrose to minimize edema. The medium was aerated with 5% CO2 in O2 before flowing through the liver in a single pass at 3.8-4.0 ml min per gram liver. Bile flow rate peaked at 10.8 μl min 20 min after portal vein cannulation and declined to 7.8 μl min 2 hr after cannulation. Liver resistance remained steady at about 70 μb per ( ml min) per liver. Some muscopic changes as well as a reduction in the dry/ wet weight ratio were detected in the liver after 2 hr of perfusion. However, a test of the perfused liver with 14C-imipramine indicated that these changes are not serious enough to substantially impair the metabolism and elimination of xenobiotics during at least the first 90 min of perfusion. Since the perfusate passes only once through the liver, drugs can be administered at a constant rate until steady state conditions are approximated. Hence, this technique not only allows the hepatic first-pass effect to be easily determined, but also permits the ready detection of pathways of metabolism and/or elimination affected by controlled changes in experimental protocol, such as the introduction of a second drug. © 1979.