Modeling Methadone Pharmacokinetics in Rats in Presence of P-glycoprotein Inhibitor Valspodar

Abstract

To quantify the in vivo role of P-glycoprotein (P-gp) in the pharmacokinetics of methadone after intravenous and oral administration, using valspodar as a P-gp inhibitor. Methadone plasma concentrations after intravenous (0.35 mg/kg) and oral (6 mg/kg) administration were analyzed, in absence and presence of valspodar, using nonlinear mixed effects modeling (NONMEM V). Non-parametric bootstrap analysis and posterior predictive check were employed as model evaluation techniques. The pharmacokinetics of methadone in the rat was successfully modeled using a two-compartmental model with a linear elimination from the central compartment and a first-order absorption process with lag time. Valspodar increased methadone F by 122% (95%CI: 34-269%) and decreased the V ( c ) and V ( p ) by 35% (95%CI: 16-49%) and 81% (95%CI: 63-93%), respectively. No effect of valspodar on other pharmacokinetic parameters was discernible. The non-parametric bootstrap analysis confirmed the absence of bias on the parameter estimates, and visual predictive check evidence the adequacy of the model to reproduce the observed time course of methadone plasma concentrations. Valspodar increased methadone's bioavailability as consequence of P-gp inhibition, which resulted in an increased analgesic effect of methadone.