We investigated the pharmacokinetics of
etoposide given to a patient suffering from multifocal liver
metastases from an
unknown primary tumor. The
drug was given either by i.v. infusion or by hepatic arterial infusion (HAI). The calculated pharmacokinetic parameters (mean values +/- SD) were similar after i.v. infusion and HAI, viz., 6.4 +/- 0.7 versus 6.5 +/- 0.2 h for the terminal elimination half-life (t1/2 beta), 98.5 +/- 1.3 versus 101.3 +/- 5.9 mg l(-1) h for the area under the plasma concentration-time curve (AUC), 21.2 +/- 0.3 versus 20.6 +/- 1.2 ml min-1 m-2 for clearance (Cl), 17.7 +/- 1.9 versus 18.1 +/- 2.6 mg/l for the peak concentration, and 11.7 +/- 1.3 versus 11.6 +/- 1.01/m2 for the volume of distribution (Vd), respectively. We therefore conclude that administration of
etoposide by HAI does not result in a significantly higher liver extraction. Hepatic extraction of
etoposide is determined by the fraction of non-
protein-bound (free)
drug present. The lack of a difference between the two administration routes suggests that under in vivo conditions the equilibrium between free and bound
drug is established before the
drug reaches the hepatic arterioles. Consequently, administration by HAI does not lead to an increased exposure of the
tumor in the liver to free (active)
etoposide. Furthermore, the overall exposure of the liver to total (bound + free)
etoposide is increased only from about 100 to 120 mg l-1 h. These results do not favor the use of this more complex route of
drug administration in the treatment of (metastatic)
cancer located in the liver.