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Tolfenamic acid is a potent CYP1A2 inhibitor in vitro but does not interact in vivo: correction for protein binding is needed for data interpretation

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Objective

Our aim was to correlate the in vitro and in vivo CYP1A2 inhibition potential of tolfenamic acid, an NSAID highly (99.7%) bound to plasma proteins, to study the significance of protein binding of inhibitor in metabolic drug interactions.

Methods

The effect of tolfenamic acid on CYP1A2 (phenacetin O-deethylation) was studied using human liver microsomes, with and without albumin (0–10 mg/ml). In a randomized, crossover study, 10 volunteers took 200 mg tolfenamic acid or placebo t.i.d. for 3 days. On day 2, a caffeine test was performed. On day 3, each ingested 4 mg of the CYP1A2 substrate tizanidine. Plasma tizanidine, its metabolites (M) and tolfenamic acid, and pharmacodynamic variables were measured.

Results

Tolfenamic acid strongly inhibited phenacetin-O-deethylation in vitro (IC50 1.8 μM without albumin). Albumin decreased its inhibitory effect in a concentration-dependent manner; the IC50 exceeded 100 μM with 10 mg/ml of albumin. Tolfenamic acid had no effect on the area under the concentration-time curve \({\left( {{\text{AUC}}_{{0 - \infty }} } \right)}\), peak concentration, time of peak concentration or half-life of tizanidine or M-3; only the \({\text{AUC}}_{{0 - \infty }} \) of secondary metabolite M-4 was slightly decreased (13%, P = 0.004). The caffeine test and the pharmacodynamic effects of tizanidine were unchanged.

Conclusions

Tolfenamic acid potently inhibits CYP1A2 in vitro when studied without albumin, but not in vivo. This apparent discrepancy is due to the high protein binding of tolfenamic acid. To avoid overestimation of the interaction potential, the inhibitory effect of highly albumin-bound compounds should also be studied in vitro with albumin, or their exact unbound plasma concentration should be used in predictions.

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Acknowledgements

This study was supported by grants from the Helsinki University Central Hospital Research Fund, the National Technology Agency, and the Sigrid Jusélius Foundation, Finland. None of the authors has any financial or personal relationships that could be perceived as influencing the research described. The experiments comply with the current laws of Finland.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 4, 00290, Helsinki, Finland

    Marjo J. Karjalainen, Pertti J. Neuvonen & Janne T. Backman

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  1. Marjo J. Karjalainen
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  2. Pertti J. Neuvonen
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  3. Janne T. Backman
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Correspondence to Janne T. Backman.

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Karjalainen, M.J., Neuvonen, P.J. & Backman, J.T. Tolfenamic acid is a potent CYP1A2 inhibitor in vitro but does not interact in vivo: correction for protein binding is needed for data interpretation. Eur J Clin Pharmacol 63, 829–836 (2007). https://doi.org/10.1007/s00228-007-0335-z

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