[Pharmacology of regional chemotherapy of colorectal liver metastases]

Abstract

Regional chemotherapy offers a means to enhance the local efficacy of an otherwise ineffective systemic chemotherapy. The regional concentration advantage of a drug is proportional to its total body clearance and inversely proportional to the blood flow through the organ. Regional infusion of adriamycin, cisplatin, methotrexate, and mitomycin C has only a small concentration advantage. Due to their high body clearance, the fluorinated pyrimidines floxuridine (FUDR) and 5-fluorouracil (5-FU) enable a high regional concentration advantage with a factor > 50 in comparison to their systemic application. Kinetic studies during isolated liver perfusion (ILP) proved that the extraction capacity of the liver is saturated at 5-FU concentrations > 10(-4) M. In the closed system of ILP, the liver removes 11.2 +/- 1.9 mg 5-FU per minute. During hepatic artery infusion the extraction of 5-FU and mitoxantrone is always incomplete. Therefore, we could detect considerable amounts of these drugs in the systemic circulation. Our investigations of 5-FU show that with higher doses and with high flow rates possibly effective and at least in single cases toxic serum levels can be obtained even during regional application. In the future, in case of hepatic artery infusion for colorectal liver metastases for example, pharmacokinetic measurements will enable the adjustment of dose and flow rate of antineoplastic drugs to benefit from their regional concentration advantage and from likewise effective systemic levels.