5-Fluorouracil Concentrations in Rat Plasma, Parotid Saliva, and Bile and Protein Binding in Rat Plasma

Abstract

The pharmacokinetics of 5-fluorouracil were studied over a 60-min period in rats that received 12.5, 25.0, and 50.0mg/kg iv. The plasma concentration–time relationship and the detectability in bile and parotid saliva (a route of elimination heretofore given little or no attention) were examined. Protein binding of 5-fluorouracil at concentrations chosen to approximate those found in plasma was determined by equilibrium dialysis. Bile–plasma and parotid saliva–plasma concentration ratios were calculated. 5-Fluorourac.il concentrations were quantitated by high-performance liquid chromatography. Plasma concentrations at all doses studied appeared to rapidly decline. The half-life, however, at the 50.0-mg/kg dose (27min) was significantly longer (p<0.025) than the corresponding half-life at the 25.0-mg/kg dose (22min). This may be attributed to an easily saturable hepatic degradation. Although an observed decline in bile–plasma and parotid saliva–plasma concentration ratios at higher doses may represent saturation of these excretary routes, the small amounts of 5-fluorouracil detected in bile and parotid saliva probably contribute negligibly to the elimination of the total drug equivalents administered. Parotid saliva–plasma concentration ratios were not useful in predicting plasma protein binding as determined by equilibrium dialysis. Excretion of intravenously administered 5-fluorouracil in saliva, however, exposes the upper GI tract to this agent and may play a part in causing stomatitis in patients receiving the drug by this route.