title: Modeling methadone pharmacokinetics in rats in presence of P-glycoprotein inhibitor valspodar.
abstract: 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.
authors: Department of Pharmacology, University of the Basque Country, Leioa, Vizcaya, Spain.
authors: Ignacio
authors: I
authors: Ortega
authors: Monica
authors: M
authors: Rodriguez
authors: Elena
authors: E
authors: Suarez
authors: Juan Jose
authors: JJ
authors: Perez-Ruixo
authors: Rosario
authors: R
authors: Calvo
mesh_terms: 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
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D003524:Cyclosporins; C070272:valspodar; D008691:Methadone