RT Journal Article
SR Electronic
T1 <em>CYP2C9</em>*<em>1B</em> Promoter Polymorphisms, in Linkage with <em>CYP2C19</em>*<em>2</em>, Affect Phenytoin Autoinduction of Clearance and Maintenance Dose
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 599
OP 611
DO 10.1124/jpet.109.161026
VO 332
IS 2
A1 Chaudhry, Amarjit S.
A1 Urban, Thomas J.
A1 Lamba, Jatinder K.
A1 Birnbaum, Angela K.
A1 Remmel, Rory P.
A1 Subramanian, Murali
A1 Strom, Stephen
A1 You, Joyce H.
A1 Kasperaviciute, Dalia
A1 Catarino, Claudia B.
A1 Radtke, Rodney A.
A1 Sisodiya, Sanjay M.
A1 Goldstein, David B.
A1 Schuetz, Erin G.
YR 2010
UL http://jpet.aspetjournals.org/content/332/2/599.abstract
AB 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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics