Pharmacokinetics and toxicity of repeated oral etoposide is altered by morphine coadministration in rats

Abstract

The influence of morphine (MOR) on the pharmacokinetics and toxicity of repeated etoposide (ETP) oral administration was evaluated in rats. A decrease in the number of leukocytes in blood was observed by 5 days of treatment with ETP (30 mg/kg/day), which was prolonged by oral MOR coadministration (30 mg/kg/day). Furthermore, MOR significantly decreased animal viability. During the dosing period, the individual plasma ETP concentrations decreased at every dose. These doses were used to estimate the individual pharmacokinetic parameters by the Bayesian method using a linear 2-compartment model with a first-order kinetic absorption and the population parameters reported in our previous study. As a result, repeated ETP dosing without MOR showed a significant decrease in the intestinal absorption rate constant (ka), and single MOR coadministration induced an increase in bioavailability (F) and decrease in ka. However, repeated coadministration of ETP suppressed the increase of F by MOR, and the dose-normalized area under the concentration-time curve was not significantly decreased. The estimated trough concentration in the final day of coadministration was significantly higher than that of the control treatment and indicated a prolonged exposure time. These changes in the absorption of ETP may be closely related to variation in P-glycoprotein (P-gp) activity in the intestine and indicate that the pharmacokinetics and toxicity of ETP are altered by repeated oral coadministration of MOR.