On the differential affinities of two anticancer analogues to their target.

The aim of the present study was to compare the pharmacokinetics of 5-fluorouracil (FU) and 5-fluoro-2-deoxyuridine (FUDR) during intra-arterial infusion. For this purpose 10 patients with widespread metastatic disease of the liver received implantable hepatic arterial catheters through the gastroduodenal artery. The patients were given FU (7.5 mg/kg) and FUDR (0.75 mg/kg) respectively via the hepatic catheter; drugs were administered for 30 min at a constant infusion rate. Blood samples were drawn from the hepatic vein after the end of the intra-arterial infusion. An established HPLC method was used to determine drug plasma levels. The patients who were on the FU infusion protocol during the first week showed mean FU plasma levels of 10 micrograms/ml, whereas FUDR plasma levels in the same patients, treated in the second week, were about 1 microgram/ml. Apparently hepatic removal was equally effective, with 97% of FU and with 96% of FUDR being extracted from the plasma. Kinetic consideration of the these data, however, suggested significantly differing affinities--on analogy with enzyme kinetics--of active facilitated transport mechanisms towards FUDR (KD = 4.2 X 10(-2)) and towards FU (KD = 64.2 X 10(-2)).