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CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose.

Publication ,  Journal Article
Chaudhry, AS; Urban, TJ; Lamba, JK; Birnbaum, AK; Remmel, RP; Subramanian, M; Strom, S; You, JH; Kasperaviciute, D; Catarino, CB; Radtke, RA ...
Published in: J Pharmacol Exp Ther
February 2010

The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide interindividual variability in clearance explained in part by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects receiving phenytoin maintenance therapy with a CYP2C9*1/*1 and CYP2C19*1/*2 genotype, we hypothesized that CYP2C9 regulatory polymorphisms (rPMs), G-3089A and -2663delTG, in linkage disequilibrium with CYP2C19*2 were responsible. These rPMs explained as much as 10% of the variation in phenytoin maintenance dose in epileptic patients, but were not correlated with other patients' warfarin dose requirements or with phenytoin metabolite ratio in human liver microsomes. We hypothesized the rPMs affected CYP2C9 induction by phenytoin, a pregnane X receptor (PXR), and constitutive androstane receptor (CAR) activator. Transfection studies showed that CYP2C9 reporters with wild-type versus variant alleles had similar basal activity but significantly greater phenytoin induction by cotransfected PXR, CAR, and Nrf2 and less Yin Yang 1 transcription factor repression. Phenytoin induction of CYP2C9 was greater in human hepatocytes with the CYP2C9 wild type versus variant haplotype. Therefore, CYP2C9 rPMs affect phenytoin-dependent induction of CYP2C9 and phenytoin metabolism in humans, with an effect size comparable with that for CYP2C9*2 and 2C9*3. These findings may also be relevant to the clinical use of other PXR, CAR, and Nrf2 activators.

Duke Scholars

Published In

J Pharmacol Exp Ther

DOI

EISSN

1521-0103

Publication Date

February 2010

Volume

332

Issue

2

Start / End Page

599 / 611

Location

United States

Related Subject Headings

  • Warfarin
  • Promoter Regions, Genetic
  • Polymorphism, Single Nucleotide
  • Phenytoin
  • Pharmacology & Pharmacy
  • Molecular Sequence Data
  • Microsomes, Liver
  • Liver
  • Linkage Disequilibrium
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chaudhry, A. S., Urban, T. J., Lamba, J. K., Birnbaum, A. K., Remmel, R. P., Subramanian, M., … Schuetz, E. G. (2010). CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose. J Pharmacol Exp Ther, 332(2), 599–611. https://doi.org/10.1124/jpet.109.161026
Chaudhry, Amarjit S., Thomas J. Urban, Jatinder K. Lamba, Angela K. Birnbaum, Rory P. Remmel, Murali Subramanian, Stephen Strom, et al. “CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose.J Pharmacol Exp Ther 332, no. 2 (February 2010): 599–611. https://doi.org/10.1124/jpet.109.161026.
Chaudhry AS, Urban TJ, Lamba JK, Birnbaum AK, Remmel RP, Subramanian M, et al. CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose. J Pharmacol Exp Ther. 2010 Feb;332(2):599–611.
Chaudhry, Amarjit S., et al. “CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose.J Pharmacol Exp Ther, vol. 332, no. 2, Feb. 2010, pp. 599–611. Pubmed, doi:10.1124/jpet.109.161026.
Chaudhry AS, Urban TJ, Lamba JK, Birnbaum AK, Remmel RP, Subramanian M, Strom S, You JH, Kasperaviciute D, Catarino CB, Radtke RA, Sisodiya SM, Goldstein DB, Schuetz EG. CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose. J Pharmacol Exp Ther. 2010 Feb;332(2):599–611.
Journal cover image

Published In

J Pharmacol Exp Ther

DOI

EISSN

1521-0103

Publication Date

February 2010

Volume

332

Issue

2

Start / End Page

599 / 611

Location

United States

Related Subject Headings

  • Warfarin
  • Promoter Regions, Genetic
  • Polymorphism, Single Nucleotide
  • Phenytoin
  • Pharmacology & Pharmacy
  • Molecular Sequence Data
  • Microsomes, Liver
  • Liver
  • Linkage Disequilibrium
  • Humans