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Liver Enzyme Decreases Drug Metabolism

white pills and a pill bottle

Genetic tests are available for the two principal alleles of CYP2C9. Researchers found a null allele of CYP2C9 that decreases metabolism of both warfarin and phenytoin and a second deleterious allele reported in African-Americans on warfarin. Collaborative clinical studies have shown that metabolism of tolbutamide, phenytoin, and warfarin are altered in people with genetic polymorphisms of CYP2C9, affecting dosage requirements and sometimes causing dangerous or fatal bleeding episodes in patients on warfarin as an anticoagulant.


In 2010, the U.S. Food and Drug Administration issued a boxed warning label for Plavix, an anti-blood-clotting medication. The warning informs health-care professionals that genetic tests are available to determine the potential effectiveness of this drug in different individuals.

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Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, Miners JO, Birkett DJ, Goldstein JA. 1996. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism.  Pharmacogenetics 6(4):341-349. [Abstract]

Kidd RS, Curry, TB Gallagher S, Edeki T, Blaisdell J and Goldstein JA. 2001. Identification of a new null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 11(9):803-809. [Abstract]

Kidd RS, Straughn AB, Meyer MC, Goldstein JA, Dalton JT. 1999. Pharmacokinetics of chlorpheniramine, phenytoin, glipizide, and nefedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics 9(1):71-80. [Abstract]

Lee CR, Pieper JA, Hinderliter AL, Blaisdell JA, Goldstein JA. 2002. Evaluation of P4502C9 metabolic activity with tolbutamide in CYP2C9*1 heterozygotes.  Clin Pharmacol Ther 72(5):562-571. [Abstract]   [Full Text]

Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, Goldstein JA. 2003. Tolbutamide, flurbiprofen and losartan as probes of CYP2C9 activity in humans. J Clin Pharmacol 43(1):84-91. [Abstract]   [Full Text]

Lee CR, Pieper JA, Hinderliter AL, Blaisdell JA, Goldstein JA. 2003. Losartan and E3174 pharmacokinetics in cytochrome P450 2C9*1/*1, *1/*2, and *1/*3 individuals. Pharmacotherapy 23(6):720-725. [Abstract] [Full Text]

Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, Goldstein JA. 2003. Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2, and *1/*3 genotypes. Eur J Clin Pharmacol 58(12):791-794. [Abstract] [Full Text]

Blaisdell J, Jorge-Nebert LF, Coulter S, Ferguson SS, Chanas B, Xi T, Mohrenweiser H, Ghanayem B, Goldstein, JA. 2004. Discovery of new potentially defective alleles of human CYP2C9. Pharmacogenetics. 14(8):527-537. [Abstract]

Delozier TC, Lee SJ, Coulter SJ, Goh BC, Goldstein JA. 2005. Functional Characterization of novel allelic variants of CYP2C9 recently discovered in Southeast Asians. J Pharmacol Exp Ther 315(3):1085-1090. [Abstract] [Full Text]

Limdi NA, McGwin G, Goldstein JA, Baird MF, Rivers CA, and Acton RT. 2008. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin. Clin Pharmacol Ther 83(2):312-321. [Abstract] [Full Text]

Limdi NA, McGwin G, Goldstein JA, Beasley TM, Adler BK, Acton RT, Arnett DK. 2008. Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulant attainment and maintenance dose among European American and African Americans. Pharmacogenomics. 9(5):511-526. [Abstract] [Full Text]

Limdi NA, Beasley TM, Crowley MR, Goldstein JA, Rieder MJ, Flockhart DA, Arnett DK, Liu N. 2008. VKORC1 polymorphisms, haplotypes and haplotype-groups on warfarin dose among African-Americans and European-Americans. Pharmacogenomics 9(10):1445-1458. [Abstract] [Full Text]

Goldstein JA, Blaisdell JA, Limdi NA. 2009. A potentially deleterious new CYP2C9 polymorphism identified in an African American patient with major hemorrhage on warfarin therapy. Blood Cells Mol Dis 42(2):155-159. [Abstract] [Full Text]

Limdi NA, Wiener H, Goldstein JA, Acton RT, Beasyley TM. 2009. Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy. Blood Cells Mol Dis 43(1):119-28. [Full Text]

Limdi NA, Beasley TM, Baird MF, Goldstein JA, McGwin G, Arnett DK, Acton RT, Allon M. 2009. Kidney function influences warfarin dose, anticoagulation control and hemorrhagic complications. J Am Soc Nephrol 20(4):912-921. [Full Text]

Goldstein JA. 2001. Invited review: Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 52:349-355. [Full Text]

Lee CR, Goldstein JA, Pieper JA. 2002. Cytochrome P450 2C9 Polymorphisms. A comprehensive review of the in vitro and human data. Pharmacogenetics. 12(3):251-263. [Abstract]

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