Hepatic conversion of 1-(tetrahydro-2-furanyl)-5-fluorouracil into 5-fluorouracil in patients with hepatocellular carcinoma

Summary

The pharmacokinetics of l-(tetrahydro-2-furanyl)-5-fluorouracil (FT) and its conversion into 5-fluorouracil (FUra) in liver tissue were studied in ten patients with hepatocellular carcinoma (HCC). The plasma concentration of FT after its intravenous injection (dosage: 800 mg) was computerfitted to a biexponential function (C= Ae^-αt Be^-βt), indicating a two-compartment disposition. The pharmacokinetic parameters did not significantly differ between the five patients with, and the five without cirrhosis of the liver. The plasma concentrations of FUra likewise showed no significant difference between the two groups.

The rates of FT degradation in the liver tissue homogenate were similar for four of the patients with cirrhosis (0.10 ± 0.05 μmol/g liver protein/30 min) and four of those without it (0.13 ±0.05). The rates of cytochrome P-450-dependent FUra formation in the microsomal fraction of liver tissue from two patients (1.1 and 1.3 nmol/mg microsomal protein/30 min) were dramatically reduced to less than half of those of two control subjects (2.4 and 2.7). The estimated rates of FUra formation in the soluble fraction (105,000 × g supernatant fraction) from the two patients (0.1 and 0.13 nmol/mg protein/30 min) were almost identical to those from the controls (0.12 and 0.14), suggesting that the rate in the soluble fraction from HCC patients may not be as strongly affected as the rate in the microsomal fraction. The soluble fraction-catalyzed rates per gram of liver protein in the two patients (58 and 67 nmol/g liver protein/30 min) were approximately twice the microsomal fraction-catalyzed rates (28.1 and 34.0), while the former rates in the controls (73 and 76) were very similar to the latter (72.5 and 84.9). These findings suggest that the soluble fraction accounts for a major portion of the capacity for converting FT to FUra in the liver of HCC patients.