CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose.
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.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Amarjit S
AS
Chaudhry
Thomas J
TJ
Urban
Jatinder K
JK
Lamba
Angela K
AK
Birnbaum
Rory P
RP
Remmel
Murali
M
Subramanian
Stephen
S
Strom
Joyce H
JH
You
Dalia
D
Kasperaviciute
Claudia B
CB
Catarino
Rodney A
RA
Radtke
Sanjay M
SM
Sisodiya
David B
DB
Goldstein
Erin G
EG
Schuetz
D000925:Anticoagulants / Q000008:administration & dosage; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics*; D001483:Base Sequence; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy; D005838:Genotype; D056945:Hep G2 Cells; D006801:Humans; D015810:Linkage Disequilibrium; D008099:Liver / Q000201:enzymology; D008862:Microsomes, Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D010672:Phenytoin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014859:Warfarin / Q000008:administration & dosage
D000925:Anticoagulants; D000927:Anticonvulsants; D014859:Warfarin; D010672:Phenytoin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19