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Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors

ABSTRACT

The required dose of the oral anticoagulant warfarin varies greatly, and overdosing often leads to bleeding. Warfarin is metabolised by cytochrome P450 enzymes CYP2C9, CYP1A2 and CYP3A. The target cell level of warfarin may be dependent on the efflux pump P-glycoprotein, encoded by the adenosine triphosphate-binding cassette gene ABCB1 (multidrug resistance gene 1). Genetic variability in CYP2C9, CYP3A5 and ABCB1 was analysed in 201 stable warfarin-treated patients using solid-phase minisequencing, pyrosequencing and SNaPshot. CYP2C9 variants, age, weight, concurrent drug treatment and indication for treatment significantly influenced warfarin dosing in these patients, explaining 29% of the variation in dose. CYP3A5 did not affect warfarin dosing. An ABCB1 haplotype containing the exon 26 3435T variant was over-represented among low-dose patients. Thirty-six patients with serious bleeding complications had higher prothrombin time international normalised ratios than 189 warfarin-treated patients without serious bleeding, but there were no significant differences in CYP2C9, CYP3A5 or ABCB1 genotypes and allelic variants.

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Figure 1

Abbreviations

ABC:

adenosine triphosphate-binding cassette

BW:

bodyweight

CYP:

cytochrome P450

dNTP:

deoxynucleotide triphospate

GLM:

generalised linear models procedure in SAS

LS means:

least-squares means

MDR:

multidrug resistance

P-GP:

P-glycoprotein

PT INR:

prothrombin time international normalised ratio

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Acknowledgements

We thank all participating patients, nurses and doctors, especially RN Ulla Prosén and RN Marine Sundin. We are indebted to Drs Hans-Göran Hårdemark and Anders Carlsson for helping to hunt down the cases. Dr Pär Hallberg is thanked for interesting ideas and discussions. BSc Gunilla Frenne, Dr Sherwan Zindrou and Mr Lars Söderlund have given invaluable technical assistance. Pyrosequencing AB provided reagents for CYP3A5 genotyping. Ms Kristi Kuljus has provided statistical expertise. The Swedish Foundation for Strategic Research, the Federation of County Councils, the Tore Nilson Foundation for Medical Research, the Royal Scientific Society's Research Foundation to the memory of Margit Bäxell, and the foundations Gustaf Adolf Johansson and Mary, Åke and Hans Ländell and the clinical research support (ALF) at Uppsala University funded this study.

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Wadelius, M., Sörlin, K., Wallerman, O. et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J 4, 40–48 (2004). https://doi.org/10.1038/sj.tpj.6500220

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Keywords

  • warfarin
  • bleeding
  • CYP2C9
  • CYP3A5
  • ABCB1
  • MDR1

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