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.