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Effects of gender and moderate smoking on the pharmacokinetics and effects of the CYP1A2 substrate tizanidine

  • Pharmacokinetics and Disposition
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Abstract

Objective

We studied the effects of gender and smoking on the pharmacokinetics and effects of the cytochrome P450 (CYP) 1A2 substrate tizanidine.

Methods

Seventy-one healthy young volunteers (male and female nonsmokers, male smokers) ingested 4 mg tizanidine. Plasma concentrations and pharmacodynamics of tizanidine were measured, and a caffeine test was performed.

Results

Among nonsmokers, the peak concentration (Cmax) and area under concentration-time curve from 0 to infinity [AUC(0-∞)] of tizanidine did not differ significantly between females and males. However, the half-life (t1/2) was 9% shorter in female nonsmokers than in male nonsmokers (P < 0.05). In male smokers, the t1/2 was 10% shorter and the weight-adjusted AUC(0-∞) 33% smaller than in male nonsmokers (P < 0.05). The caffeine/paraxanthine ratio was 35–40% smaller (P = 0.001) in male smokers than in nonsmoking males or females, but did not differ between males and females. Tizanidine lowered blood pressure and caused drowsiness significantly (P < 0.05) more in females than in either male groups. The effects on blood pressure were smallest in male smokers (P < 0.05).

Conclusions

Gender by itself seems to have no clinically significant effect on the pharmacokinetics of tizanidine, whereas smoking reduces plasma concentrations and effects of tizanidine. Any possible effect of gender and smoking is largely outweighed by individual variability in CYP1A2 activity due to genetic and environmental factors and in body weight. Careful dosing of tizanidine is warranted in small females, whereas male smokers can require higher than average doses.

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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.

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Authors and Affiliations

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

    Janne T. Backman, Marika T. Schröder & Pertti J. Neuvonen

  2. Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, FI-00290, Helsinki, Finland

    Janne T. Backman

Authors
  1. Janne T. Backman
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  2. Marika T. Schröder
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  3. Pertti J. Neuvonen
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Corresponding author

Correspondence to Janne T. Backman.

Additional information

This study was supported by grants from the Helsinki University Central Hospital Research Fund, the National Technology Agency, and the Sigrid Jusélius Foundation, Finland.

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Backman, J.T., Schröder, M.T. & Neuvonen, P.J. Effects of gender and moderate smoking on the pharmacokinetics and effects of the CYP1A2 substrate tizanidine. Eur J Clin Pharmacol 64, 17–24 (2008). https://doi.org/10.1007/s00228-007-0389-y

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  • DOI: https://doi.org/10.1007/s00228-007-0389-y

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