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The influence of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Aims

Warfarin is a frequently used anticoagulant drug with narrow therapeutic index and high interindividual variability in the dose requirement. We have previously shown that warfarin dose is influenced by cytochrome P450 (CYP) 2C9 genotype, age, body weight and co-treatment with drugs that interfere with warfarin metabolism. As, in many patients, drug co-treatment cannot be avoided, we investigated the effect of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose.

Methods

Caucasian patients on stable maintenance warfarin therapy with CYP2C9*1/*1 genotype (n=82) were included in the study. Plasma concentrations of (S)- and (R)-warfarin as well as warfarin hydroxylated metabolites were determined using HPLC assay and corresponding clearances of (S)- and (R)-warfarin were calculated.

Results

Patients co-treated with carbamazepine (n=5) had significantly higher plasma 10-hydroxywarfarin concentrations than patients not taking any interacting drugs (n=54) (median: 0.327 μg/ml vs 0.030 μg/ml, p=0.003). (S)- and (R)-warfarin clearances were also higher in the carbamazepine co-treated group (p=0.003), as were warfarin dose requirements (median: 9.00 mg/day vs 3.86 mg/day, p=0.003). Under the conditions of this study, patients co-treated with amiodarone (n=6) did not differ significantly regarding any measured characteristic from patients with no interacting drug treatment, while patients co-treated with simvastatin or lovastatin (n=17) had lower 10-hydroxywarfarin concentration (p=0.02).

Conclusions

We confirmed important interaction between carbamazepine and warfarin metabolism which can be of major clinical importance. If treatment with carbamazepine cannot be avoided, patients taking warfarin should be frequently monitored, especially when initiating or stopping carbamazepine therapy.

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Authors and Affiliations

  1. Institute of Biochemistry, Faculty of Medicine, Vrazov trg 2, SI-1000, Ljubljana, Slovenia

    Darja Herman, Katja Breskvar & Vita Dolžan

  2. Faculty of Pharmacy, Ljubljana, Slovenia

    Igor Locatelli, Iztok Grabnar & Aleš Mrhar

  3. Department of Vascular Diseases, University Medical Centre, Ljubljana, Slovenia

    Polona Peternel & Mojca Stegnar

  4. Department of Internal Medicine, General Hospital Murska Sobota, Murska Sobota, Slovenia

    Mitja Lainščak

Authors
  1. Darja Herman
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  2. Igor Locatelli
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  3. Iztok Grabnar
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  4. Polona Peternel
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  5. Mojca Stegnar
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  9. Vita Dolžan
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Correspondence to Vita Dolžan.

Additional information

This work was financially supported by the Ministry of Education, Science and Sport of Slovenia (Grants No. PO-0503-0381, P1-0170 and P1-0189-0787).

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Herman, D., Locatelli, I., Grabnar, I. et al. The influence of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose. Eur J Clin Pharmacol 62, 291–296 (2006). https://doi.org/10.1007/s00228-006-0104-4

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  • DOI: https://doi.org/10.1007/s00228-006-0104-4

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