1) The study examined 105 epilepsy patients on phenytoin (PHT) monotherapy and found a significant association between the CYP2C9*3 allele and PHT toxicity in the North Indian population.
2) While the CYP2C9*2 allele was not correlated with PHT toxicity, the CYP2C9*3 allele was significantly associated with PHT toxicity, with 59.25% of cases having the *1/*1 genotype compared to 86.27% of controls.
3) The results suggest the CYP2C9*3 polymorphic allele may cause PHT toxicity in the North Indian population.
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1. Our study shows that polymorphic allele CYP2C9*3 might be causing PHT toxicity
in North Indian population while CYP2C9*2 allele has not any correlation with PHT
toxicity.
INTRODUCTION
The study was conducted in the Department of Neurology, PGIMER, Chandigarh
from period July 2012 to July 2014 and approved by Institute Ethics Committee
PGIMER.
105 patients with epilepsy on PHT monotherapy were recruited (Dosage - 5mg/
kg).
DNA was extracted from blood using Phenol-Chloroform-Isoamylalcohal method
and genotyping of CYP2C9 *2 (rs1799853) C430T and CYP2C9*3 (rs1057910)
A1075C alleles was performed using Taqman based Real Time-PCR (CAT NO.
4362691 - Applied Biosystems).
54 patients with PHT associated side effects were recruited as cases while 51 pa-
tients who did not experience any PHT associated adverse effect served as con-
trols.
For CYP2C9*2 allele - Genotypic frequency of cases was 81.4 for *1/*1, 11%
for *1/*2 and 7.4% for *2/*2, whereas in controls 80.4% for *1/*1, 13.7% for
*1/*2 and 5.9% for *2/*2 was identified (p=0.886) (Table-I).
For CYP2C9*3 allele - Genotypic frequency of cases was 59.25% for *1/*1,
35.18% for *1/*3 and 5.55% for *3/*3, whereas in controls 86.27% for *1/*1,
13.72% for *1/*3 and 0.0% for *3/*3 was identified (p=0.005).
Significant association of CYP2C9*3 allele with PHT toxicity was found in the
North Indian population (p<0.05) (Table-II).
ROLE OF CYP2C9*3 ALLELE IN EPILEPSY PATIENTS EXPERIENCING
PHENYTOIN TOXICITY
Vivek Kumar Garg1
, Madhu Khullar 2
, Bikash Medhi 3
, Manish Modi 1
PGIMER, Chandigarh
OBJECTIVE
To find association of polymorphic CYP2C9 *2 and *3 alleles with phenytoin
toxicity in North Indian epileptic patients.
Epilepsy is one of the most common, chronic, heterogeneous neurological disor-
der characterized by repeated unprovoked seizures.
It affects 1-2% of the population worldwide. However, the prevalence of epi-
lepsy is 0.5%-1% in India and 0.87% in Chandigarh.1
Phenytoin (PHT), Carbamazepine, Phenobarbital and Valproic Acid are primary
antiepileptic drugs (AEDs). However, adverse drug reactions to these AEDs are
reported in 5-10% of the patients.2
Of these AEDs, PHT is associated with various ADRs such as diplopia, dizzi-
ness, sedation, ataxia and nystagmus. PHT is metabolized by CYP2C9 (90%)
and CYP2C19 (10%) and polymorphism in these genes produces ADRs.3
Hence, detection of CYP2C9 *2/*3 and CYP2C19 *2/*3 polymorphisms may
help predict susceptibility to toxicity in Indian patients.3
RESULTS
Genotypes PHT toxicity
(N=54)
Drug responsive patients (N=51)
Wild 44 (81.4%) 41 (80.4%)
Heterozygous variant 6 (11%) 7 (13.7%)
Homozygous variant 4 (7.4%) 3 (5.9%)
p- value 0.886
Genotypes PHT toxicity
(N=54)
Drug responsive patients (N=51)
Wild 32 (59.25%) 44 (86.27%)
Heterozygous variant 19 (35.18%) 7 (13.72%)
Homozygous variant 3 (5.55%) 0 (0.0%)
p- value 0.005
REFERENCES
TABLE-I
TABLE-II
MATERIALS & METHODS
CONCLUSIONS
1.Bhathena A, Spear BB. Pharmacogenetics: improving drug and dose selection. Curr
Opin Pharmacol 2008; 8:639-46.
2. Perucca E, Meador KJ. Adverse effects of antiepileptic drugs. Acta Neurol Scand
(Suppl.) 2005;181:30-35
3. Kesavan R, Narayan SK, Adithan C. Influence of CYP2C9 and CYP2C19 genetic
polymorphisms on phenytoin induced neurological toxicity in Indian epileptic patients.
Eur J Clin Pharmacol 2010;66:689‑96.
Figure 2: Genotypic frequency
of CYP2C9*3 allele.
Wild type (*1/*1)
Heterozygous variant (*1/*3)
Homozygous variant (*3/*3)
Figure 1: Genotypic frequency
of CYP2C9*2 allele.
Wild type (*1/*1)
Heterozygous variant (*1/*2)
Homozygous variant (*2/*2)
ACKNOWLEDGEMENT
This work was financially supported by Indian Council of Medical Research (ICMR),
New Delhi, INDIA.