Research ArticlesMulticompartment Pharmacokinetic Model of 4′-Demethylepipodophyllotoxin 9-(4,6-O-Ethylidene- β-D-glucopyranoside) in Humans

The formation and elimination of the metabolite of 4′-demethylepipodophyllotoxin 9-(4,6-O-ethylidene-β-D-glucopyranoside) (I) were studied in seven patients with advanced cancer who received I intravenously. The plasma concentration–time data best fit a triexponential equation. The volume of the metabolite compartment (27.5 liters) was calculated as a fraction of the extrapolated volume. A larger body clearance (111.7 ml/min) of metabolite as compared to the renal clearance (31.3 ml/min) indicates that the metabolite is lost from the plasma equivalent space by another elimination route. The combination of metabolite data presented here with previously published data for unchanged I leads to a multicompartment model for the distribution, metabolism, and excretion of I and its metabolite. A comparison of algebraically derived model transfer constants with those evaluated by computer fitting the system of differential equations is presented.