The Annals of Pharmacotherapy: Vol. 37, No. 3, pp. 454. DOI 10.1345/aph.1C025a
© 2003 Harvey Whitney Books Company.
Comment: patient-specific factors predictive of warfarin dosage requirements
Jonatan D Lindh, MD
PhD Student, Resident in Clinical Pharmacology Department of Clinical
Pharmacology, C1 68 Huddinge University Hospital S-141 86 Stockholm Sweden FAX
46-8-58581070 E-mail
jonatan.lindh{at}hs.se
Published Online, February 3, 2003. www.theannals.com, DOI 10.1345/aph.1C025a
TO THE EDITOR: Absher et
al.1
investigated factors influencing warfarin dose requirements in 146 patients
with stable international normalized ratios and warfarin doses. Along with
several factors of known importance, they identified African American
ethnicity as an independent predictor of warfarin requirements >5 mg/d,
presumably due to genetic differences. In this context, they discussed the
isoenzyme CYP2C9 as a gene of possible interest, but discarded this
explanation because all known mutations of the CYP2C9 gene reduce
S-warfarin metabolism, resulting in a lower, not higher, warfarin
dose requirement. This conclusion seems to depend on the assumption that such
mutations should be more frequent in the African American than in the white
American population. However, this is not the case. The mutated CYP2C9 allele
frequency has been estimated to be 0.015 in African Americans and 0.14 in
white
Americans.2
Hence, only 3% of African Americans carry 1 or 2 mutated CYP2C9 alleles,
whereas 26% of whites are affected.
Both heterozygous and homozygous mutations of CYP2C9 are known to
significantly reduce the warfarin
requirement.3
Consequently, the scarcity of mutated CYP2C9 alleles in African Americans
would be expected to substantially increase the probability of a high dose
requirement compared with the white population, where mutations are abundant.
The findings of Absher et al. confirm this prediction, although the possible
influence of other interethnic differences cannot be excluded.
References
- Absher RK, Moore ME, Parker MH. Patient-specific factors predictive
of warfarin dosage requirements. Ann Pharmacother 2002;36:1512-7.[Abstract]
- Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS,
Shenfield GM, et al. The role of the CYP2C9-Leu359 allelic variant in the
tolbutamide polymorphism. Pharmacogenetics 1996;6:341-9.[Medline]
- Loebstein R, Yonath H, Peleg D, Almog S, Rotenberg M, Lubetsky A,
et al. Interindividual variability in sensitivity to warfarin — nature
or nurture? Clin Pharmacol Ther 2001;70:159-64.[CrossRef][Medline]
Related articles in The Annals:
- Authors' Reply
- Randall K Absher, M Elisabeth Moore, and Mary H Parker
The Annals 2003 37: 454.
[Full Text]
