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Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model

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Abstract

Rationale

P-glycoprotein (P-gp) plays an important role in the efflux of drugs from the brain back into the bloodstream and can influence the pharmacokinetics and pharmacodynamics of drug molecules. To our knowledge, no studies have reported pharmacodynamic effects of any antidepressant drug in the P-gp knockout mice model.

Objective

The aim of this study was to investigate the enantiomeric venlafaxine and metabolite concentrations in serum and brain of abcb1ab (−/−) mice compared to wild-type mice upon chronic dosing, and to assess the effect of venlafaxine treatment on open-field behavior.

Methods

P-gp knockout and wild-type mice received two daily intraperitoneal injections of venlafaxine (10 mg/kg) over ten consecutive days. Locomotor and rearing activities were assessed on days 7 and 9. After 10 days, drug and metabolite concentrations in brain and serum were determined using an enantioselective LC/MS/MS method.

Results

The brain concentrations of venlafaxine and its three demethylated metabolites were two to four times higher in abcb1ab (−/−) mice compared to abcb1ab (+/+) mice. The behavioral results indicated an impact on exploration-related behaviors in the open-field as center activity was increased, and rears were decreased by venlafaxine treatment.

Conclusion

Our results show that P-gp at the blood–brain barrier plays an important role in limiting brain entry of the enantiomers of venlafaxine and its metabolites after chronic dosing. Taken together, the present pharmacokinetic and pharmacodynamic findings offer the possibility that the expression of P-gp in patients may be a contributing factor for limited treatment response.

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Acknowledgments

This work was supported by grants from Östergötland County Council (LK), the German Research Foundation (CH, US; Hi 399/6-1), the Swedish Research Council (FB, JA, FCK; 2009-4740), and the National Board of Forensic Medicine in Sweden (FCK).

Conflicts of interest

None.

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Authors and Affiliations

  1. Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden

    Louise Karlsson, Björn Carlsson, Johan Ahlner, Finn Bengtsson & Fredrik C. Kugelberg

  2. Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany

    Christoph Hiemke & Ulrich Schmitt

  3. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, SE-587 58, Linköping, Sweden

    Martin Josefsson, Johan Ahlner & Fredrik C. Kugelberg

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  1. Louise Karlsson
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  2. Christoph Hiemke
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  3. Björn Carlsson
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  4. Martin Josefsson
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  5. Johan Ahlner
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  6. Finn Bengtsson
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  7. Ulrich Schmitt
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  8. Fredrik C. Kugelberg
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Corresponding author

Correspondence to Fredrik C. Kugelberg.

Additional information

Ulrich Schmitt and Fredrik C. Kugelberg share the last authorship.

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Karlsson, L., Hiemke, C., Carlsson, B. et al. Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model. Psychopharmacology 215, 367–377 (2011). https://doi.org/10.1007/s00213-010-2148-5

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  • DOI: https://doi.org/10.1007/s00213-010-2148-5

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