RT Journal Article
SR Electronic
T1 <em>CYP2C9*1B</em> promoter polymorphisms, in linkage with <em>CYP2C19*2</em>, affect phenytoin auto-induction 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 jpet.109.161026
DO 10.1124/jpet.109.161026
A1 Amarjit S. Chaudhry
A1 Thomas J. Urban
A1 Jatinder K. Lamba
A1 Angela K. Birnbaum
A1 Rory P. Remmel
A1 Murali Subramanian
A1 Stephen Strom
A1 Joyce H. You
A1 Dalia Kasperaviciute
A1 Claudia B. Catarino
A1 Rodney A. Radtke
A1 Sanjay M. Sisodiya
A1 David B. Goldstein
A1 Erin G. Schuetz
YR 2009
UL http://jpet.aspetjournals.org/content/early/2009/10/23/jpet.109.161026.abstract
AB The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide inter-individual variability in clearance explained partially by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects on phenytoin maintenance therapy with a CYP2C9*1/*1 &amp; 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 PXR and CAR activator. Transfection studies showed CYP2C9 reporters with wild-type versus variant alleles had similar basal activity but significantly greater PHT induction by co-transfected PXR, CAR and Nrf2 and less YY1 repression. Phenytoin induction of CYP2C9 was greater in human hepatocytes with the CYP2C9 wild-type vs. variant haplotype. Therefore, CYP2C9 rPMs affect phenytoin-dependent induction of CYP2C9 and phenytoin metabolism in humans, with an effect size comparable to that for CYP2C9*2 and 2C9*3. These findings may also be relevant to the clinical use of other PXR, CAR and Nrf2 activators.The American Society for Pharmacology and Experimental Therapeutics