Quantification of absorption, intestinal and hepatic first pass effect in a chronic dog model

A chronic dog model was used to measure the absorption and to elucidate the site and extent of presystemic metabolism of a selective D1-agonist (CY 208-243). The dog was instrumented with portal vein and carotid artery catheters together with an electromagnetic flow measuring device around the portal vein. After administering [14C]CY 208-243 intrajejunally, absorption rate was defined as the product of porto-arterial substrate difference and portal venous blood flow. The extent of absorption amounted to 34% for total radioactivity and 31% for unchanged drug, this indicating a gastrointestinal first-pass of 9%. In an additional study [14C]CY 208-243 was injected intravenously to the dog; the absorption (29%) and the bioavailability (5%) of CY 208-243 were calculated from the ratio of dose normalized, oral versus intravenous AUC values for total radioactivity and unchanged drug, respectively. These data confirm the absorption value found with the chronic dog model and indicate a global presystemic, i.e. intestinal and hepatic, first-pass effect of 83%. In conclusion, this chronic dog model allows an accurate assessment of drug absorption and a quantification of the gastrointestinal and hepatic first-pass effects.