Skip to main content
Log in

Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine–alprazolam interaction in patients with psychosomatic disease

  • Pharmacokinectics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript



Fluvoxamine (FVX) is metabolized by cytochrome P450 (CYP) 2D6 and CYP1A2 and inhibits CYP3A4. The aim of this study was to investigate the factors responsible for interindividual variability in the extent of interaction between FVX and alprazolam (ALP).


Blood samples were taken from 49 depressive patients to determine plasma concentration of FVX, ALP or both. Twenty-four samples were taken during the FVX-alone period, 21 samples during the ALP-alone period and 30 samples during the FVX-ALP period. Subjects were also genotyped for CYP2D6.


The concentration-to-dose (C/D) ratio of ALP during the FVX-treatment period was significantly higher than that during the ALP-alone period. The CYP2D6 genotype affected neither the C/D ratios of FVX nor the extent of interaction. The mean C/D ratio of FVX in smokers was reduced by more than 30% in comparison with that in non-smokers. The mean C/D ratio of ALP in non-smokers was increased by FVX, while that in smokers was unchanged.


The extent of interaction between FVX and ALP may be affected by smoking, which alters the C/D ratio of FVX. Therefore, when FVX and ALP are concomitantly administered, it should be noted that non-smokers may exhibit greater drug interaction than smokers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others


  1. Sproule BA, Naranjo CA, Brenmer KE, Hassan PC (1997) Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of the evidence. Clin Pharmacokinet 33:454–471

    Article  PubMed  CAS  Google Scholar 

  2. Fleishaker JC, Hulst LK (1994) A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 46:35–39

    Article  PubMed  CAS  Google Scholar 

  3. Suzuki Y, Shioiri T, Muratake T, Kawashima Y, Sato S, Hagiwara M, Inoue Y, Shimoda K, Someya T (2003) Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles. Eur J Clin Pharmacol 58:829–833

    PubMed  CAS  Google Scholar 

  4. Carrillo JA, Dahl ML, Svensson JO, Alm C, Rodriguez I, Bertilsson L (1996) Disposition of fluvoxamine in humans is determined by the polymorphic CYP2D6 and also by the CYP1A2 activity. Clin Pharmacol Ther 60:183–190

    Article  PubMed  CAS  Google Scholar 

  5. Ohara K, Tanabu S, Ishibashi K, Ikemoto K, Yoshida K, Shibuya H (2003) CYP2D6*10 alleles do not determine plasma fluvoxamine concentration/dose ratio in Japanese subjects. Eur J Clin Pharmacol 58:659–661

    PubMed  CAS  Google Scholar 

  6. Schmith VD, Cox SR, Zemaitis MA, Kroboth PD (1991) New high-performance liquid chromatographic method for the determination of alprazolam and its metabolites in serum: instability of 4-hydroxyalprazolam. J Chromatogr B 568:253–260

    Article  CAS  Google Scholar 

  7. Eap CB, Gaillard N, Powell K, Baumann P (1996) Simultaneous determination of plasma levels of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine by gas chromatography-mass spectrometry. J Chromatogr B 682:265–272

    Article  CAS  Google Scholar 

  8. Ieiri I, Yamada S, Seto K, Morita T, Kaneda T, Mamiya K, Tashiro N, Higuchi S, Otsubo K (2003) A CYP2D6 phenotype-genotype mismatch in Japanese psychiatric patients. Pharmacopsychiat 36:192–196

    Article  CAS  Google Scholar 

  9. Kubota T, Yamaura Y, Ohkawa N, Hara H, Chiba K (2000) Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes. Br J Clin Pharmacol 50:31–34

    Article  PubMed  CAS  Google Scholar 

  10. von Moltke LL, Greenblatt DJ, Court MH, Duan SX, Harmatz JS, Shader RI (1995) Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 15:125–131, 1995

    Article  Google Scholar 

  11. Spigset O, Granberg K, Hagg S, Norstrom A, Dahlqvist R (1997) Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms. Eur J Clin Pharmacol 52:129–133

    Article  PubMed  CAS  Google Scholar 

  12. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M (1994) Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 46:452–459

    PubMed  CAS  Google Scholar 

  13. Han XM, Ou-Yang DS, Lu PX, Jiang CH, Shu Y, Chen XP, Tan ZR, Zhou HH (2001) Plasma caffeine metabolite ratio (17X/137X) in vivo associated with G-2964A and C734A polymorphisms of human CYP1A2. Pharmacogenetics 11:429–435

    Article  PubMed  CAS  Google Scholar 

  14. Otani K, Yasui N, Kaneko S, Ohkubo T, Osanai T, Sugawara K, Hayashi K, Chiba K, Ishizaki T (1997) Effects of genetically determined S-mephenytoin 4-hydroxylation status and cigarette smoking on the single-dose pharmacokinetics of oral alprazolam. Neuropsychopharmacology 16:8–14

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Yasufumi Sawada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sugahara, H., Maebara, C., Ohtani, H. et al. Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine–alprazolam interaction in patients with psychosomatic disease. Eur J Clin Pharmacol 65, 699–704 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: