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Isobolographic analysis of interaction between drugs with nonparallel dose–response relationship curves: a practical application

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Abstract

The objective of this study was to characterize the anticonvulsant and acute adverse-effect potentials of topiramate (TPM) and gabapentin (GBP)—two second-generation antiepileptic drugs administered alone and in combination in the maximal electroshock (MES)-induced seizures and chimney test in mice. The anticonvulsant and acute adverse effects of the combination of TPM with GBP at the fixed ratio of 1:1 were determined using the type I isobolographic analysis for nonparallel dose–response relationship curves (DRRCs). To ascertain any pharmacokinetic contribution to the observed interaction between TPM and GBP, total brain concentrations of both drugs were determined. The isobolographic analysis of interaction for TPM and GBP, whose DRRCs were not parallel in both MES and chimney tests, was accompanied with a presentation of all required calculations allowing the determination of lower and upper lines of additivity. The isobolographic analysis revealed that TPM combined with GBP at the fixed-ratio combination of 1:1 interacted supraadditively (synergistically) in terms of suppression of MES-induced seizures, and simultaneously, the combination produced additive interaction with respect to motor coordination impairment (adverse effects) in the chimney test. The evaluation of pharmacokinetic characteristics of interaction for the combination of TPM with GBP revealed that neither TPM nor GBP affected their total brain concentrations in experimental animals, and thus, the observed interaction in the MES test was pharmacodynamic in nature. In conclusion, the combination of TPM with GBP, because of supraadditivity in the MES test and additivity in terms of motor coordination impairment in the chimney test as well as lack of pharmacokinetic interactions between drugs, fulfilled the criterion of a favorable combination, worthy of recommendation in further clinical practice.

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Abbreviations

AED:

antiepileptic drug

DRRC:

dose–response relationship curve

GBP:

gabapentin

MES:

maximal electroshock seizure test

TPM:

topiramate

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Acknowledgements

I would like to express my gratitude to Prof. Ronald J. Tallarida (Temple University School of Medicine, Philadelphia, USA) for his stimulating hints and help during the preparation of the isobolograms. I would also like to thank to Mr. Wojciech Zgrajka (Institute of Agricultural Medicine, Lublin, Poland) for the skillful determination of the brain concentrations of GBP. This study was supported by a grant (DS 345/2003–2005) from the Medical University of Lublin.

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  1. Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland

    Jarogniew J. Luszczki

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  1. Jarogniew J. Luszczki
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Correspondence to Jarogniew J. Luszczki.

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Luszczki, J.J. Isobolographic analysis of interaction between drugs with nonparallel dose–response relationship curves: a practical application. Naunyn-Schmied Arch Pharmacol 375, 105–114 (2007). https://doi.org/10.1007/s00210-007-0144-z

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  • DOI: https://doi.org/10.1007/s00210-007-0144-z

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