European Journal of Clinical Pharmacology

, Volume 62, Issue 6, pp 431–436 | Cite as

Effects of fluvastatin and cigarette smoking on CYP2C9 activity measured using the probe S-warfarin

  • Myong-Jin Kim
  • Anne N. Nafziger
  • Angela D. M. Kashuba
  • Julia Kirchheiner
  • Steffen Bauer
  • Andrea Gaedigk
  • Joseph S. BertinoJr
Pharmacogenetics
First Online:
Received:
Accepted:

Abstract

Objective

The effect of cigarette smoking on CYP2C9 activity is unknown. We conducted a study to evaluate whether there is a difference in CYP2C9 activity in smokers versus non-smokers by examining S-warfarin AUC after CYP2C9 inhibition with fluvastatin. In addition, the effect of the CYP2C9 inhibitor fluvastatin was evaluated using S-warfarin as a probe.

Methods

A randomized, single dose, two-treatment crossover study of warfarin with a washout period of 21 days was performed. Eighteen healthy Caucasian smokers and non-smokers, genotyped as CYP2C9*1/*1 or CYP2C9*1/*2, received warfarin 10 mg plus vitamin K 10 mg to measure baseline CYP2C9 activity. Warfarin dosing was repeated after 18 days of fluvastatin 40 mg twice daily to evaluate CYP2C9 activity after inhibition.

Results

The S-warfarin \({\text{AUC}}_{{0 - \infty }}\) between smokers and non-smokers did not differ by >25% after inhibition. There was no difference in S-warfarin \({\text{AUC}}_{{0 - \infty }}\) during baseline (p=0.45) or inhibition (p=0.19) periods for smokers versus non-smokers. Fluvastatin increased the AUC of S-warfarin by 42±29% and 26±18% in smokers and nonsmokers, respectively. Linear regression analyses showed significant but weak correlations between peak concentrations (Cat 1 h) or (−) 3S,5R-fluvastatin AUC0–12 h and extent of warfarin inhibition. For (+) 3R,5S-fluvastatin, a weak correlation was found between Cat 1 h and extent of warfarin inhibition.

Conclusions

Cigarette smoking does not affect CYP2C9 activity as evaluated using S-warfarin as a CYP2C9 probe. Fluvastatin is a weak inhibitor of CYP2C9 activity in both smokers and non-smokers.

Keywords

Cigarette smoking CYP2C9 Fluvastatin S-warfarin  
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Notes

Acknowledgements

The authors acknowledge Carrie Vyhlidal, Ph.D. for her expert review of the manuscript.

Conflict of interest statement

Dr Bertino is a consultant for Merck and Janssen Ortho-McNeil. He has received research funding from Merck, Janssen Ortho-McNeil, Pfizer and Glaxo SmithKline. Dr. Nafziger is a consultant for Merck and Merck Schering-Plough. She has received research funding from Merck, Pfizer and Glaxo SmithKline. Dr. Kashuba is a consultant for Boehringer Ingelheim and Roche. She has received research funding from Abbott, GlaxoSmithKline, and Gilead.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Myong-Jin Kim
    • 1
  • Anne N. Nafziger
    • 1
    • 2
  • Angela D. M. Kashuba
    • 3
  • Julia Kirchheiner
    • 4
  • Steffen Bauer
    • 5
  • Andrea Gaedigk
    • 6
  • Joseph S. BertinoJr
    • 1
    • 2
  1. 1.Clinical Pharmacology Research Center, Bassett HealthcareCooperstownUSA
  2. 2.Ordway Research Institute Drug Development CenterAlbanyUSA
  3. 3.School of PharmacyUniversity of North CarolinaChapel HillUSA
  4. 4.Department of PharmacologyUniversity of CologneCologneGermany
  5. 5.Institute of Clinical PharmacologyUniversity Medicine Berlin,Charité, Campus Charité MitteBerlinGermany
  6. 6.Section of Clinical Pharmacology and Experimental TherapeuticsThe Children’s Mercy HospitalKansasUSA

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