Steady-State NonlinearPharmacokineticsof 5-FluorouracilduringHepatic Arterialand IntravenousInfusionsin CancerPatients1
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چکیده
Hepatic arterial catheters were placed for therapy in 8 patients with primary or metastatic liver cancer. Temporary hepatic ve nous catheters allowed direct sampling of blood for hepatic venous drug concentrations. Patients were administered from three to six infusions at rates of 10, 30, 90, 135, 180, 210, and 270 mg/kg/day (0.053 to 1.43 ¿¿M/kg/min), given over 2 h, of 5fluorouracil (FUra). In Method 1, FUra was infused i.V., and FUra was measured in plasma from hepatic arterial and hepatic venous blood. In Method 2, FUra was given i.v. at one time and infused into hepatic arterial blood at another time, and FUra was mea sured in plasma from peripheral blood at the same site in both cases. Steady-state FUra plasma concentrations were measured by a sensitive and specific high-performance liquid chromatography method. Data were computer fitted to the equations appropriate for a physiological two-compartment flow model with Michaelis-Menten elimination from the peripheral compartment and blood flow rate, 0, between the central and peripheral compartment. Methods 1 and 2 gave mean Vmaxand Km values which did not differ significantly; the overall mean Vmaxwas 2.02 MM/kg/min, and the overall mean Kmwas 10.9 ^M. For Method 1 the mean Qi value was 0.0803 liters/(kg x min) or 5.26 liters/ min, which is the same as cardiac output, but for Method 2 the mean Q2 value was higher, namely 0.189 liters/(kg x min) or 13.0 liters/min. Steady-state systemic and intrinsic clearances and extraction ratios decreased progressively as the dose rate increased. Intraand inter-subject variation of both Vmai<and Km were of the same order of magnitude. As a result, dose rate escalation should be conservative for dose rates above 135 mg/ kg/day. The results support hepatic arterial infusion as a means of improving the therapeutic index of FUra in the treatment of cancer of the liver.
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