Psychopharmacology

, Volume 183, Issue 4, pp 490–499 | Cite as

Population pharmacokinetic analysis of drug–drug interactions among risperidone, bupropion, and sertraline in CF1 mice

  • Jun-Sheng Wang
  • C. Lindsay DeVane
  • B. Bryan Gibson
  • Jennifer L. Donovan
  • John S. Markowitz
  • Hao-Jie Zhu
Original Investigation

Abstract

Rationale

Accumulating evidence indicates that modulation of the activity of cytochrome P450 (CYP) enzymes and the multidrug resistance transporter P-glycoprotein (P-gp) is responsible for many drug–drug interactions.

Objectives

The potential interaction of risperidone (RISP), which is metabolized by 2D6 and transported across the blood brain barrier (BBB) by P-gp, was studied in combination with bupropion (BUP) and also with sertraline (SERT).

Methods

BUP, SERT, and RISP were administered intraperitoneally into CF1 mice at doses of 100, 10, and 1 μg/g mouse, respectively. Plasma and brain samples were collected at timed intervals from 0.5 to 6 h. A pharmacokinetic analysis was performed using both traditional compartmental modeling and a population pharmacokinetic approach.

Results

BUP increased the RISP plasma (5.9-fold, P<0.01) and brain (2.2-fold, P<0.01) area under the drug concentration vs time curve (AUC), but did not alter the brain-to-plasma concentration ratio. SERT did not significantly change the plasma AUC of RISP and 9-hydroxy-RISP, but increased the brain AUC of RISP and 9-hydroxy-RISP 1.5-fold (P<0.05) and 5-fold (P<0.01), respectively. RISP did not produce significant alterations of plasma or brain concentrations of BUP. It increased the plasma AUC and elimination half-life (T 1/2e) of desmethyl-SERT 12.5-fold (P<0.01) and 107-fold (P<0.01), respectively.

Conclusions

These results suggest that pharmacokinetic interactions exist among these three psychoactive drugs involving inhibition of drug metabolizing enzymes and/or P-gp and other drug transporters present in the BBB. The mechanisms and consequences of these interactions require further study in humans to establish clinical relevance.

Keywords

Bupropion Sertraline Risperidone Cytochrome P450 P-glycoprotein Blood brain barrier 

Notes

Acknowledgements

This work was supported by a grant from Janssen Pharmaceutica and by NIH Grant MH071811-01. None of the authors has conflicting interests that interfere with the integrity of the content of the article.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Jun-Sheng Wang
    • 1
  • C. Lindsay DeVane
    • 1
    • 3
  • B. Bryan Gibson
    • 1
  • Jennifer L. Donovan
    • 1
  • John S. Markowitz
    • 2
  • Hao-Jie Zhu
    • 1
    • 2
  1. 1.Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral SciencesMedical University of South CarolinaCharlestonUSA
  2. 2.Department of Pharmaceutical SciencesMedical University of South CarolinaCharlestonUSA
  3. 3.Institute of PsychiatryMedical University of South CarolinaCharlestonUSA

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