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A new hepatic artery infusion model.

3660 Background: The role of hepatic artery infusion (HAI) has been controversial, and its use often has been empiric without the benefit of pharmacologic and toxicologic data because a suitable animal model that incorporates prolonged HAI has not been available. The goal of this study is to develop an HAI model nearly identical to humans and to employ this model to evaluate hepatic toxicity for site directed chemotherapy. In such a model, various tumor agents other than the traditional FUDR could be evaluated rapidly for dose determination and timing of administration.


METHODS
The Yucatan minipig possesses a cytochrome P450 enzyme family with remarkable similarities to the human and microscopic and gross anatomy that also resembles the human liver. In this development program, an hepatic artery catheter was placed via the gastroduodenal artery (GDA) in eight pigs. Continuous infusion of saline was maintained for one to four weeks to establish baseline information. Liver biopsies were done at the time of laparotomy for catheter placement and subsequently laparoscopic biopsies were performed at various intervals. Morphological evaluation of the organ was accomplished using light and transmission electron microscopy (TEM) and biochemically by direct measurment of P450 activity. Serum liver function studies were included in the overall assessment.


RESULTS
We were able to maintain an HAI catheter in the GDA for extended infusion periods to simulate human chemotherapy treatment protocols. Infusion of saline via HAI established baseline controls of TEM, light microscopy histology, and P450 activity levels. Data will be reported for these controls and some experimental animals.


CONCLUSIONS
This HAI animal model allows for evaluation of hepatic toxicity of various cytotoxic agents at the cellular, subcellular, and biochemical level. Adverse interactions between drugs being administered simultaneously with hepatic artery infusion and susceptible to metabolic transformation by the P450 enzyme system can be identified readily with this model. It may be possible to study the underlying causes of sclerosing cholangitis commonly associated with FUDR. Supported by the Falk Medical Trust and Baxter International No significant financial relationships to disclose.