Skip to main content

Advertisement

Log in

Effect of ketoconazole on venlafaxine plasma concentrations in extensive and poor metabolisers of debrisoquine

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

Abstract

Objective

To study the influence of CYP3A4 inhibition by ketoconazole on the disposition of venlafaxine in individuals with different CYP2D6 pheno- and genotypes.

Methods

In an open two-phase study, 21 healthy volunteers with known CYP2D6 pheno- and genotype [14 extensive metabolisers (EMs), 7 poor metabolisers (PMs)] were given a single oral dose of venlafaxine (50 mg to EMs and 25 mg to PMs). Plasma and urine levels of venlafaxine and its three metabolites were measured and the pharmacokinetics of venlafaxine were determined. After a 2-week washout period, subjects were treated for 2 days with ketoconazole (100 mg twice daily) starting 1 day before the administration of venlafaxine; and the same parameters as for the administration of venlafaxine only were measured.

Results

Data were evaluated from 20 subjects (14 EMs and 6 PMs) who completed the study. The dose-corrected AUC of venlafaxine was on average 2.3 times higher (P<0.01) and that of its active metabolite O-desmethylvenlafaxine 3.4 times lower (P<0.0001) in PMs than EMs. There was a good correlation between the debrisoquine metabolic ratio and the ratio between the AUC of venlafaxine and that of O-desmethylvenlafaxine (Rs=0.93, P<0.002). The majority of subjects showed higher plasma levels of venlafaxine and O-desmethylvenlafaxine upon co-administration of ketoconazole. AUC of venlafaxine significantly increased by 36% and that of O-desmethylvenlafaxine by 26% (P<0.01). Cmax values increased by 32% and 18%, respectively. The elimination half-life of venlafaxine was unaltered. Three of the PMs displayed marked increases in AUC (81, 126 and 206%) and Cmax (60, 72, 119%) of venlafaxine while the other three showed small or no changes.

Conclusions

Ketoconazole consistently affected the disposition of venlafaxine in EMs of debrisoquine while the response in PMs was erratic. The precise mechanisms underlying this interaction remain to be elucidated.

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.

Institutional subscriptions

Fig. 1.

Similar content being viewed by others

References

  1. Fogelman SM, Schmider J, Venkatakrishnan K, von Moltke LL, Harmatz JS, Shader RI, Greenblatt DJ (1999) O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants. Neuropsychopharmacology 20:480–490

    CAS  PubMed  Google Scholar 

  2. Otton SV, Ball SE, Cheung SW, Inaba T, Rudolph RL, Sellers EM (1996) Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol 41:149–156

    CAS  PubMed  Google Scholar 

  3. Fukuda T, Nishida Y, Zhou Q, Yamamoto I, Kondo S, Azuma J (2000) The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population. Eur J Clin Pharmacol 56:175–180

    CAS  PubMed  Google Scholar 

  4. Mahgoub A, Idle JR, Dring DG, Lancaster R, Smith RL (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet 2:584–586

    CAS  PubMed  Google Scholar 

  5. Skoda RC, Gonzalez FJ, Demierre A, Meyer UA (1988) Two mutant alleles of the human cytochrome P450 db1 gene (P450,II, D1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci U S A 85:5240–5243

    CAS  PubMed  Google Scholar 

  6. Heim M, Meyer UA (1990) Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 336:529–532

    CAS  PubMed  Google Scholar 

  7. Dahl ML, Johansson I, Porsmyr-Palmertz M, Ingelman-Sundberg M, Sjöqvist F (1992) Analysis of the CYP2D6 gene in relation to debrisoquine and desipramine hydroxylation in Swedish population. Clin Pharmacol Ther 51:12–17

    CAS  PubMed  Google Scholar 

  8. Veefkind AH, Haffmans PM, Hoencamp E (2000) Venlafaxine serum levels and CYP2D6 genotype. Ther Drug Monit 22:202–208

    CAS  PubMed  Google Scholar 

  9. Lessard E, Yessine MA, Hamelin BA, O'Hara G, LeBlanc J, Turgeon J (1999) Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. Pharmacogenetics 9:435–443

    CAS  PubMed  Google Scholar 

  10. Johansson I, Lundqvist E, Bertilsson L, Dahl M-L, Sjöqvist F, Ingelman-Sundberg M (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci U S A 90:11825–11829

    CAS  PubMed  Google Scholar 

  11. Böttiger Y, Tybring G, Götharsson E, Bertilsson L (1997) Inhibition of the sulphoxidation of omeprazole by ketoconazole in poor and extensive metabolizers of S-mephenytoin. Clin Pharmacol Ther 62:384–391

    Google Scholar 

  12. Riley CM, James MO (1986) Determination of ketoconazole in plasma, liver, lung and adrenal of the rat by high-performance liquid chromatography. J Chromatogr 377:287–294

    Article  CAS  PubMed  Google Scholar 

  13. WinNonlin reference guide, Version 3.0. 1998–1999 Pharsight Corporation, Mountain view, CA, USA

Download references

Acknowledgement

We thank Tommy Petterson and Anneli Wahlberg for excellent help. This work is supported by the Swedish Research Council (project 3902) and Karolinska Institutet. J. Lindh is supported by the Swedish Foundation for Strategic Research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ayman AL-Shurbaji.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lindh, J.D., Annas, A., Meurling, L. et al. Effect of ketoconazole on venlafaxine plasma concentrations in extensive and poor metabolisers of debrisoquine. Eur J Clin Pharmacol 59, 401–406 (2003). https://doi.org/10.1007/s00228-003-0627-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-003-0627-x

Keywords

Navigation