New approach to the hepatic first-pass effect by whole-body autoradiography.

Abstract

Whole-body autoradiography was used to investigate the influence of the route of administration and dose on the distribution of drugs in the rat. Propranolol and imipramine were used as model drugs with a relatively high hepatic extraction ratio, and salicylic acid and antipyrine were used as model drugs with a relatively low hepatic extraction ratio. Each drug was administered at the same radioactivity level to rats by intravenous infusion or portal venous infusion over 30 s, regardless of the total dose and route of administration. An autoradiogram obtained 3 min after portal venous infusion was compared with that obtained 3 min after intravenous infusion. The radioactivity of propranolol that reached the systemic circulation was highly dependent on both the route of administration and dose, while that of imipramine was dependent only on the route in the dose range studied. The radioactivity of salicylic acid and antipyrine was distributed in the whole body independently of the route of administration and dose. The two drugs having a higher hepatic extraction ratio showed an uneven distribution in the liver after portal venous administration, but the two drugs having a lower hepatic extraction ratio did not. It was shown that the technique of portal venous administration for whole-body autoradiography is useful to visualize differences in drug distribution depending on the route of administration and dose and to study hepatic tissue binding in the first-pass extraction of drugs.