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

  • Hideyo Sugahara
  • Chiharu Maebara
  • Hisakazu Ohtani
  • Masanori Handa
  • Katsumi Ando
  • Kazunori Mine
  • Chiharu Kubo
  • Ichiro Ieiri
  • Yasufumi Sawada
Pharmacokinectics and Disposition

Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusions

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.

Keywords

Alprazolam CYP2D6 Drug interaction Fluvoxamine Polymorphism Smoking 

References

  1. 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 33:454–471PubMedCrossRefGoogle Scholar
  2. 2.
    Fleishaker JC, Hulst LK (1994) A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 46:35–39PubMedCrossRefGoogle Scholar
  3. 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 58:829–833PubMedGoogle Scholar
  4. 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 60:183–190PubMedCrossRefGoogle Scholar
  5. 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 58:659–661PubMedGoogle Scholar
  6. 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 568:253–260CrossRefGoogle Scholar
  7. 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 682:265–272CrossRefGoogle Scholar
  8. 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 36:192–196CrossRefGoogle Scholar
  9. 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 50:31–34PubMedCrossRefGoogle Scholar
  10. 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, 1995CrossRefGoogle Scholar
  11. 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 52:129–133PubMedCrossRefGoogle Scholar
  12. 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 46:452–459PubMedGoogle Scholar
  13. 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 11:429–435PubMedCrossRefGoogle Scholar
  14. 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 16:8–14PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Hideyo Sugahara
    • 1
  • Chiharu Maebara
    • 2
  • Hisakazu Ohtani
    • 3
  • Masanori Handa
    • 1
  • Katsumi Ando
    • 1
  • Kazunori Mine
    • 2
  • Chiharu Kubo
    • 1
  • Ichiro Ieiri
    • 2
  • Yasufumi Sawada
    • 3
  1. 1.Department of Psychosomatic Medicine, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical SciencesKyushu UniversityFukuokaJapan
  3. 3.Laboratory of Drug Informatics, Graduate School of Pharmaceutical SciencesThe University of TokyoBunkyo-ku, TokyoJapan

Personalised recommendations