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

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Abstract

Purpose

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.

Materials and 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.

Conclusion

Valspodar increased methadone’s bioavailability as consequence of P-gp inhibition, which resulted in an increased analgesic effect of methadone.

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Acknowledgements

Support was from University of the Basque Country (IO) and the Basque Government scholarship (MR). We are thankful to Mr. Jokin Lodos for his careful animal surgical procedures.

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Authors and Affiliations

  1. Department of Pharmacology, University of the Basque Country, Leioa, Vizcaya, Spain

    Ignacio Ortega, Elena Suarez & Rosario Calvo

  2. Dynakin S.L. Parque Tecnologico de Bizkaia, Bizkaia, Spain

    Monica Rodriguez

  3. Pharmacy and Pharmaceutics Division, Department of Engineering, Miguel Hernández University, Alicante, Spain

    Juan Jose Perez-Ruixo

  4. Clinical Pharmacology Division, Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV, Belgium, Turnhoutseweg, 30 2340, Beerse, Belgium

    Ignacio Ortega & Juan Jose Perez-Ruixo

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  1. Ignacio Ortega
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  2. Monica Rodriguez
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Correspondence to Ignacio Ortega.

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Ortega, I., Rodriguez, M., Suarez, E. et al. Modeling Methadone Pharmacokinetics in Rats in Presence of P-glycoprotein Inhibitor Valspodar. Pharm Res 24, 1299–1308 (2007). https://doi.org/10.1007/s11095-007-9251-2

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