Pharmacokinetic Assessment of Absorptive Interaction of Oral Etoposide and Morphine in Rats

Abstract

Etoposide and morphine are well known P-glycoprotein (P-gp) substrates. The pharmacokinetic effect of morphine on plasma etoposide concentration after the oral concomitant use of etoposide and morphine in rats was assessed using a population analysis approach. A P-gp substrate quinidine and the anticholinergic drug propantheline were also administered with etoposide to compare with the effects of morphine. Plasma etoposide concentration after oral administration was well described using a linear 2-compartment open model with first-order kinetic absorption from the intestine, although a flip-flop phenomenon was shown. After administration of etoposide with morphine, an increased concentration and extended time at maximum concentration were observed compared with the administration of etoposide alone. However, coadministered quinidine significantly increased the maximum concentration without changing the time of the peak concentration of etoposide. Coadministered propantheline significantly extended the time at maximum concentration, although no changes in the peak concentration of etoposide were observed. These coadministered drugs resulted in different pharmacokinetic parameters of etoposide and acted as a significant covariate. That is, morphine and quinidine significantly increased the bioavailability of etoposide believed to be due to competitive P-gp inhibition in the intestine. In contrast, morphine and propantheline decreased the absorption rate constant and were associated with the suppression of enterokinesis. These results indicate that it is necessary to understand the effects on P-gp as well as have information on other effects on the gastrointestinal tract, such as enterokinesis suppression, and to appropriately assess the pharmacokinetic interactions of the combined oral use of P-gp substrate drugs.