Nonlinear pharmacokinetic models for 5-fluorouracil in man: Intravenous and intraperitoneal routes

Abstract

A two-compartment physiologic pharmacokinetic model has been developed for 5-fluorouracil (5FU). This model, which incorporates saturable whole body clearance, satisfactorily predicts disappearance kinetics after an intravenous bolus and steady-state levels during constant intravenous infusions. A half-saturating concentration (KM) of 15 microM was determined by comparison of model simulations with literature data. Both hepatic and extrahepatic elimination can be inferred for 5FU, but the exact anatomic or compartmental location of the clearance cannot be determined from the available clinical data. The effect of venous and arterial plasma sampling is discussed. This model has been extended to include intraperitoneal and oral administration of 5FU by the addition of peritoneal fluid and liver compartments.

No effect of dose, hepatic function, or nutritional status on 5-FU clearance following continuous (5-day), 5-FU infusion

“…As reported previously, there was a significant relationship noted between the 5-FU dose and AUC (Milano et al, 1988). Several studies have reported the pharmacokinetics of 5-FU to be nonlinear with increasing 5-FU dose (Christophidis et al, 1978;McDermott et al, 1982;Collins et al, 1980). As reported by others (Erlichman et al, 1986), we found the pharmacokinetics of 5-FU following continuous infusion to be linear and clearance to be unchanged with increased 5-FU doses within a 2 fold range (550-1069 mg m2day-' x 5).…”

“…Several studies following intravenous bolus or oral administration of 5-FU have suggested the systemic clearance of 5-FU is saturable (nonlinear) with increasing 5-FU dose (Christophidis et al, 1978;McDermott et al, 1982;Collins et al, 1980). In contrast, steady-state concentrations of 5-FU have been observed to increase linearly with dose following continuously administered 5-FU (Erlichman et al, 1986).…”

Bioavailability and feasibility of subcutaneous 5-fluorouracil

“…For the calculation of the bioavailability a constant clearance has been assumed. However, as pointed out earlier it is known that the clearance of 5-FU is saturable (Collins et al, 1980). We chose a relatively high dose rate of 5-FU (250 mg /1.5 h) to increase the chance to be well above the detection limit also in case of poor s.c. absorption.…”

“…administration assuming a constant clearance. The 5-FU clearance has been described to be half-saturated (Km) at a concentration of 15 LM (1.95 tg ml-') (Collins et al, 1980 Discussion 5-FU is an important component in the treatment of a variety of solid tumours. In colorectal cancer 5-day high-dose or prolonged (several weeks) continuous low-dose infusion have shown higher response rates and were better tolerated than standard 5-day monthly bolus regimen (Seifert et al, 1975;Lokich et al, 1989).…”

Intra-abdominal fibrosis after systemic and intraperitoneal therapy containing fluoropyrimidines

“…When given by the intraperitoneal route, floxuridine (FUDR) showed an appreciable catabolic clearance mainly by the liver 16,17 and greater potency compared with 5-FU. 18 Hepatic artery infusion (HAI) of FUDR may induce hepatic fibrosis, but intra-abdominal fibrosis associated with IP FUDR has not been previously described.…”