Modeling methadone pharmacokinetics in rats in presence of P-glycoprotein inhibitor valspodar.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Valspodar increased methadone's bioavailability as consequence of P-gp inhibition, which resulted in an increased analgesic effect of methadone.
Ortega
Ignacio
I
Department of Pharmacology, University of the Basque Country, Leioa, Vizcaya, Spain.
Rodriguez
Monica
M
Suarez
Elena
E
Perez-Ruixo
Juan Jose
JJ
Calvo
Rosario
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D007262:Infusions, Intravenous; D008691:Methadone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008954:Models, Biological; D017711:Nonlinear Dynamics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D003524:Cyclosporins; C070272:valspodar; D008691:Methadone