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| ORIGINAL ARTICLE |
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| Year : 2012 | Volume
: 60
| Issue : 6 | Page : 577-580 |
Association of CYP2C9 polymorphisms with phenytoin toxicity in Indian patients
Akanksha N Thakkar, Shital R Bendkhale, Santosh R Taur, Nithya J Gogtay, Urmila M Thatte
Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
| Date of Submission | 22-Jul-2012 |
| Date of Decision | 08-Sep-2012 |
| Date of Acceptance | 24-Oct-2012 |
| Date of Web Publication | 29-Dec-2012 |
Correspondence Address:
Urmila M Thatte
Department of Clinical Pharmacology, 1st Floor, New MS Building, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra
India
 Source of Support: Department of Biotechnology and the Department of Science and Technology, Govt. of India through their FIST program, Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.105189
Background: Genetic polymorphisms of CYP2C9 can lead to wide inter-individual variations in drug metabolism. Decreased metabolism leads to higher plasma levels, causing adverse drug reactions (ADRs). Polymorphic alleles CYP2C9 * 2 and CYP2C9 * 3 occur in the Indian population and this may serve as the basis for using genotyping as a tool to predict phenytoin toxicity. Aims: To evaluate the association between the presence of polymorphic alleles CYP2C9 * 2 and *3 and phenytoin toxicity in Indian patients with epilepsy. Settings and Design: A case-control study with cases defined as those who had plasma phenytoin concentrations above 20 μg/ml. Materials and Methods: The study population included 259 patients with epilepsy on phenytoin. Phenotyping was done using High Performance Liquid Chromatography. Those with plasma phenytoin levels above 20 μg/ml were taken as cases and the rest as controls. Genotyping was done by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism. Statistics: Numerical data between groups was compared using unpaired-'t' test. Between-group comparison of categorical data was done using Chi square for trend with crude odds ratio (OR). Adjusted OR was calculated using binary logistic regression. Results: There were 40 cases and 219 controls. Mean phenytoin dosage between groups was not statistically significant. Of the 40 cases, 25 (62.5%) cases had wild alleles versus 178 (81.3%) controls. We found a significant association between polymorphic alleles CYP2C9 * 2 and *3 and toxic phenytoin levels. After adjusting for age, sex and dose, a significant association between polymorphic alleles and phenytoin toxicity was still found. Conclusions: This study shows significant association between polymorphic alleles and phenytoin toxicity in this study population. However, until technology for genotyping becomes cost-effective, we would recommend Therapeutic Drug Monitoring to guide dosing.
Keywords: CYP2C9, genotyping, phenytoin, phynetoin toxicity, polymorphic alleles
How to cite this article:
Thakkar AN, Bendkhale SR, Taur SR, Gogtay NJ, Thatte UM. Association of CYP2C9 polymorphisms with phenytoin toxicity in Indian patients. Neurol India 2012;60:577-80 |
| » Introduction | |  |
Despite the availability of newer anti-epileptic drugs (AEDs), phenytoin continues to be widely prescribed at tertiary care centers in India. [1] It has a narrow therapeutic window (10-20 μg/ml), and at levels lower than 10 μg/ml, the drug follows first order kinetics. Above 10 μg/ml, the drug follows zero order kinetics and adverse drug reactions (ADRs) become common. Neurological side-effects are dose dependent with nystagmus, diplopia, ataxia, slurred speech and impaired cognition occurring first. A further rise in drug levels may lead to cerebellar atrophy, lethargy, coma, and even precipitate status epilepticus. Other side effects include gingival overgrowth and hypersensitivity. There is wide inter-individual variability in phenytoin metabolism, which depends on the patient's age, weight, hepatic and renal function and genetic make-up. Consequently, it is difficult to predict clinically whether or not a patient is likely to suffer from phenytoin toxicity. Thus, therapeutic drug monitoring (TDM) is routinely recommended to adjust doses. [2]
Recent studies have identified genotyping as a potential tool to personalize phenytoin therapy [3],[4] and mutations in several genes are thought to predispose patients to toxicity. [5] Ninety percent of phenytoin metabolism occurs through an enzyme encoded by the gene CYP2C9, and 10% by CYP2C19. Polymorphisms in these genes may reduce drug metabolism, increase drug concentrations and thus produce ADRs. Detection of these polymorphisms à priori may help predict susceptibility to toxicity.
In South Indians, the genotype frequencies for CYP2C9 * 1/*1, *1/*2, *1/*3 and *2/*3 have been reported as 82.3%, 4.4%, 12.6% and 0.7%, respectively. [6] A North Indian study reported a similar genotype distribution in its population. [7] In view of the fact that wide inter- and intra-ethnic variability in allele distribution has been reported globally, [8],[9],[10],[11],[12] genotyping needs to be done for specific alleles in different populations. Hence, this study was conducted to identify whether an association existed between the polymorphisms of CYP2C9 and toxic levels of phenytoin in patients with epilepsy in a tertiary care center in Mumbai.
| » Materials and Methods | | |
This study was approved by the Committee for Academic Research Ethics at Seth G. S. Medical College and K. E. M. Hospital, Mumbai. Written-informed consent was obtained from all participants. The study was conducted in accordance with the "Ethical Guidelines for Biomedical Research on Human Participants" by the Indian Council of Medical Research (ICMR). [13]
Adult patients of either gender with epilepsy attending the TDM out-patient department of the KEM Hospital between June 2009 and February 2012, who had been receiving phenytoin therapy for at least 2 months, were included in the study. Participants were excluded if they were receiving any concomitant drugs likely to alter the metabolism of phenytoin (e.g., phenobarbitone, tolbutamide and valproate) or had hepatic or renal dysfunction. This was a case-control study where cases were defined as those who had plasma phenytoin levels over 20 μg/ml (as toxicity is more likely to occur above this concentration). [14] Patients with levels below 20 μg/ml acted as controls.
Five ml of venous blood was collected for genotyping in 100 μl of 10% disodium EDTA and 5 ml in heparin for plasma concentrations. Genomic DNA was extracted from leucocytes by the phenol-chloroform method and genotyping was performed by a polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) as per a method described earlier. [15],[16] Trough plasma phenytoin levels were determined using High Performance Liquid Chromatography (HPLC). [17]
Statistical analysis
Data was tested for normality using the Kolmogorov-Smirnov test. Numerical data between groups was compared using either the unpaired t test (if normally distributed) or Mann-Whitney U test (if not normally distributed). Proportion of patients with polymorphic alleles in both groups was expressed as a percentage of the total. Between-group comparison of categorical data was done using a Chi-square test at a 5% significance level and the strength of the association was tested using a crude odds ratio (OR). Adjusted OR was calculated using a binary logistic regression model where plasma concentration categorized as >20 μg/ml and >20 μg/ml was used as the dependent variable, and age, sex, phenytoin dose and genotype were the independent variables. Further, the regression analysis was used to derive an equation/model that would predict toxicity reliably. All analyses were carried out using SPSS version 16.0.
| » Results | | |
Two hundred and fifty-nine participants in total were included. Of these, 40 were cases and the rest were controls. Among the cases, 36 were males and 4 were females. Among the controls, 145 were males and 74 were females. The proportion of males was significantly higher in cases as compared to controls (P0 = 0.0047). Cases were also younger than controls by approximately 6 years (31.68 ± 10.35 vs. 37.73 ± 14.1 years; P = 0.01). The mean daily dose of phenytoin was comparable between cases and controls (P0 = 0.16). The mean dose corrected plasma phenytoin level in cases was significantly higher compared to controls (6.14 ± 2.01 (μg/ml)/(mg/kg) vs. 1.66 ± 1.17 (μg/ml)/(mg/kg); P < 0.0001) [Table 1].
| » Genotyping | | |
The overall frequency of the genotypes CYP2C9 * 1/*1, *1/*2, *1/*3 and *2/*3 was 78.38%, 8.88%, 12.36% and 0.39%, respectively. Of the cases, 25 (62.5%) were *1/*1, 3 (7.5%) were *1/*2, 11 (27.5%) were *1/*3 and 1 (2.5%) was *2/*3. Of the controls, 178 (81.3%) were *1/*1, 20 (9.1%) were *1/*2 and 21 (9.6%) were *1/*3 [Table 2]. The odds of being a case were greater for males than for females [adjusted OR, 6.24; 95% CI, 2.003 to 19.46]. Patients with *1/*3 genotype were more likely to be a case than the wild type (adjusted OR, 4.8; 95% CI, 1.89 to 12.17; P = 0.001). Polymorphic alleles were more frequent in cases than in controls (adjusted OR, 2.86; 95% CI, 1.32 to 6.18; P = 0.008).
The mean daily dose of phenytoin was comparable between mutant (*1/*2, *1/*3 and *2/*2) and wild (*1/*1) genotypes [8.8 (3.08 to 7.89) vs. 7.6 (1.54 to 9.09) mg/kg body weight; P = 0.17]. The mean dose corrected plasma phenytoin level in patients with mutant genotypes was significantly higher compared to those with wild genotypes [3.1 (0.15 to 9.46) vs. 2.1 (0.04 to 9.04) (μg/ml)/(mg/kg); P = 0.003)].
On applying binary logistic regression, the variables found to be significantly associated with toxicity were age, sex and genotype. The regression analysis yielded a model with the formula, Log (OR) = −2.202 + 1.832 (Male) - 0.036 (Age) + 0.034 (*1/*2) + 1.568 (*1/*3) + 22.338 (*2/*3). Although this model had a specificity of 97.7% and an accuracy of 84.9%, it could explain only 20% of variability in the probability of developing toxicity.
| » Discussion | | |
In the present study (40 cases and 219 controls), we found an overall frequency of polymorphic genotypes of CYP2C9 to be 8.88% (*1/*2), 12.36% (*1/*3) and 0.39% (*2/*3). We also found a significant association between the polymorphic alleles CYP2C9 * 2 and *3 and toxic levels of phenytoin.
As phenytoin is metabolized primarily by the enzymes CYP2C9 (90%) and CYP2C19 (10%), its plasma levels are in part influenced by their polymorphisms. However, several other factors (age, sex, dose, formulation, drug interactions and hepatic dysfunction) can influence plasma levels and we did find a significant association between genetic polymorphisms, sex and age and drug toxicity. After adjusting for age, sex and dose, a significant association between polymorphic alleles and phenytoin toxicity was still found.
We used in the present study, 20 μg/ml as the cut off to demarcate cases and controls. The clinical phenytoin toxicity consisted of ataxia ( n = 20), giddiness ( n = 7), diplopia ( n = 3), gingival hyperplasia ( n = 2), one case each of nystagmus, tremors and dysarthria. Some patients experienced more than one clinical symptom and hence number of toxic symptoms was higher than number of patients. Seventy percent of patients (n = 28) with levels above 20 μg/ml showed clinical signs and symptoms of toxicity or had a documented history of clinical phenytoin toxicity. It has also been shown that the CYP2C9 * 3 polymorphism caused significantly lower drug metabolism and therefore higher plasma concentrations which predisposed patients to ADRs. [18],[19] On the other hand, studies and case reports have shown an association between the *2 and *3 alleles and clinical phenytoin toxicity such as neurological and cutaneous ADRs. [20],[21],[22],[23],[24],[25] Based on these observations, we studied the CYP2C9 * 2 and *3 variants only.
We found that those with *1/*2 or *1/*3 genotypes are more likely to have serum levels above the reference range (Adjusted ORs, 1.035 and 4.8, respectively). Kesavan et al. [20] have reported a strong association between *1/*2 or *1/*3 genotypes in South Indians and neurological toxicity (Adjusted ORs, 3.5 and 15.3, respectively). This difference may be a result of differential prevalence of polymorphisms in the two populations and/or diverse definitions of toxicity used in the studies used (levels in our study versus clinical toxicity).
The present study also showed that higher phenytoin levels were more common in the younger age group. This is in contrast to previous studies which showed reduced phenytoin clearance in older individuals leading to higher plasma levels and toxicity. [26],[27] We also found that males had 6 times higher odds of developing toxicity relative to females. Kesavan et al. [20] did not find any association between gender and neurological toxicity as also by others. [28],[27]
As of this writing, 35 polymorphic alleles of CYP2C9 and 28 alleles of CYP2C19 have been identified. [29] Our study was thus limited by the fact that we looked at only two polymorphisms of CYP2C9. The RFLP methodology itself is limited by the fact that an allele which was neither a * 2 or *3 is assumed to be wild. We also did not study the serum albumin levels of the patients that can alter the level of circulating free phenytoin. The current technology available for genotyping used by us is tedious and labor intensive and also beyond the reach of the vast majority of patients that visit our center. At the moment, we thus do not think that pre-prescription genotyping should be used to predict which patient will develop toxicity until the genotyping procedure becomes cost-effective. Until then TDM at Rs 50/- done at least twice a year can help guide dosing.
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[Table 1], [Table 2]
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