This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ensminger, W. D. Articles by Frei, E. Search for Related Content PubMed PubMed Citation Articles by Ensminger, W. D. Articles by Frei, E., III

A Clinical-Pharmacological Evaluation of Hepatic Arterial Infusions of 5-Fluoro-2'-deoxyuridine and 5-Fluorouracil¹

Divisions of Clinical Pharmacology, Medical Oncology, Radiology, and Surgery, Sidney Farber Cancer Institute, Boston, Massachusetts 02115

We have attempted to evaluate the degree to which hepatic arterial infusion of 5-fluoro-2'-deoxyuridine (FdUrd) or 5-fluorouracil produces higher hepatic and lower systemic drug concentrations than are achieved with corresponding peripheral venous infusions. Hepatic arterial catheters were placed for therapy in 15 patients with primary or metastatic liver cancer. Temporary hepatic venous catheters allowed direct sampling of drug levels in the hepatic venous effluent as well as measurement of hepatic blood flow. FdUrd was measured primarily by radioimmunoassay and fluorouracil by a high-pressure liquid chromatographic system. Due to the limited sensitivities of these assays, short (40 to 60 min) infusions at dose rates 10 to 100 times those conventionally used were given in order to produce drug levels that could be measured reliably. Even at dose rates of 0.5 to 40 mg/kg of body weight/hr for FdUrd and 5.6 mg/kg of body weight/hr for fluorouracil, steady state drug levels were achieved in the bloodstream in 30 to 40 min and hepatic extraction could be quantified.

The hepatic extraction of FdUrd is high with an extraction ratio (hepatic arterial level — hepatic venous level/hepatic arterial level) of 0.69 to 0.92 and a clearance of 0.81 to 2.3 liters/min. The hepatic extraction of fluorouracil, however, appears to be lower with an extraction ratio of 0.22 to 0.45 and a clearance of 0.24 to 0.45 liters/min. With hepatic arterial drug infusion, 94 to 99% of FdUrd and 19 to 51% of fluorouracil is extracted in one pass. Hepatic venous levels, which are one measure of intrahepatic drug concentration in the hepatic and tumor capillary bed, were 4-fold higher for FdUrd infusion and 1.5-fold higher for fluorouracil infusion when drug was given by the hepatic arterial route. Systemic FdUrd levels with hepatic arterial infusion were only about 25% of corresponding systemic levels with peripheral venous infusion. Systemic fluorouracil levels with hepatic arterial infusion were also lower and were about 60% of corresponding systemic levels with peripheral venous infusion.

These results support hepatic arterial infusion as a means to improve the therapeutic index of FdUrd and fluorouracil in the treatment of cancer in the liver. Although molar equivalent dose rates of FdUrd and fluorouracil were used in this study, the differences in FdUrd and fluorouracil pharmacology as noted above may not be applicable to conventional hepatic arterial therapy where much lower dose rates are used. Nonetheless, this type of analytical approach should prove valuable in the evaluation of other agents for hepatic arterial chemotherapy.

¹ These investigations supported in part by NIH Grants CA-19589 and N01-CM-67037 to the Sidney Farber Cancer Institute.

² To whom requests for reprints should be addressed, at Simpson Memorial Institute, 102 Observatory, University of Michigan Medical Center, Ann Arbor, Michigan 48109.

Received 3/ 2/78. Accepted 8/11/78.

This article has been cited by other articles:

				N. Kemeny Presurgical Chemotherapy in Patients Being Considered for Liver Resection Oncologist, July 1, 2007; 12(7): 825 - 839. [Abstract] [Full Text] [PDF]