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To separately assess intestinal and hepatic first-pass effects with absorption ratio data, we have established an experimental model of rats double-cannulated into the portal and jugular veins. The model allows us to take blood samples simultaneously from conscious rats that have recovered from surgical damage. Double cannulation did not alter the physiological and hematological conditions. Moreover, the plasma concentration profiles of unchanged drug following oral and intravenous administration in the double-cannulated rats were not different from those of rats single-cannulated into the jugular vein. These results suggest that the model can be useful for separately assessing intestinal and hepatic first-pass effects. We evaluated the first-pass effects in the intestine and the liver separately using this model. S-1452, as a model drug with 94% absorption ratio, was administered intravenously and orally to the double-cannulated rats, and the drug concentrations in the portal and systemic plasma were determined, and the rates of elimination from the intestine and liver were estimated. In the first pass, approximately 26% and 56% of the dose were extracted by the intestine and liver, respectively. This method, in which the animal is not restricted nor under anesthesia, allows us to obtain reliable values of individual first pass effects in the intestine and liver. This method can also be an effective tool for assessing the site and extent of drug-drug interaction on the first-pass effects. |
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