Association of polymorphisms of CYP2C9, CYP2C19, and ABCB1, and activity of P-glycoprotein with response to anti-epileptic drugs

Epilepsy, the most common neurological disorder, has treatment failure rate of 20 to 25%. Inter-individual variability in drug response can be attributed to genetic polymorphism in genes encoding different drug metabolizing enzymes, drug transporters (P-gp), and enzymes involved in sodium channel bi...

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Bibliographic Details
Published in:	Journal of postgraduate medicine Vol. 60; no. 3; pp. 265 - 269
Main Authors:	Taur, S R, Kulkarni, N B, Gandhe, P P, Thelma, B K, Ravat, S H, Gogtay, N J, Thatte, U M
Format:	Journal Article
Language:	English
Published:	India Medknow Publications and Media Pvt. Ltd 01-07-2014 Medknow Publications & Media Pvt. Ltd
Subjects:	Adolescent Adult Aged Anticonvulsants Anticonvulsants - administration & dosage Anticonvulsants - pharmacology ATP Binding Cassette Transporter 1 - genetics ATP-Binding Cassette, Sub-Family B, Member 1 - genetics Biomedical research Carbamazepine - administration & dosage Carbamazepine - pharmacology Confidence intervals Cross-Sectional Studies Cytochrome P-450 CYP2C19 - genetics Cytochrome P-450 CYP2C9 - genetics Dosage and administration Drug dosages Drug resistance Drug Resistance - genetics Drug therapy Enzymes Epilepsy Epilepsy - drug therapy Epilepsy - genetics Epilepsy - metabolism Female Gene Frequency Genetic aspects Genetic polymorphisms Genetic Variation Genotype Humans Logistic Models Male Middle Aged Mortality Pharmacogenetics Plasma Polymorphism, Restriction Fragment Length Studies Young Adult India
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Summary:	Epilepsy, the most common neurological disorder, has treatment failure rate of 20 to 25%. Inter-individual variability in drug response can be attributed to genetic polymorphism in genes encoding different drug metabolizing enzymes, drug transporters (P-gp), and enzymes involved in sodium channel biosynthesis. The present study attempted to evaluate association of polymorphisms of CYP2C9, CYP2C19, and ABCB1, and P-gp activity with treatment response in patients with epilepsy. Patients with epilepsy on phenytoin and/or phenobarbital and/or carbamazepine were categorized into responders and non-responders as per the International League Against Epilepsy. Plasma drug concentration was estimated by high-performance liquid chromatography. P-gp activity was measured by flow cytometry using rhodamine efflux. The polymerase chain reaction (PCR-RFLP) was used to study polymorphisms of ABCB1 (C3435T), CYP2C9 (416 C > T, and 1061 A > T), and CYP2C19 (681 G > A and 636 G > A). Of total 117 patients enrolled in this study, genotype data was available for 115 patients. P-gp activity was higher in non-responders (n = 68) compared to responders (n = 47) (P<0.001). No association of 416 C > T and 1061 A > T in CYP2C9 or 681 G > A and 636 G > A in CYP2C19 was observed with response phenotype in genotypic analysis. Significant genotypic (odds ratio, OR = 4.5; 95% CI, 1.04 to 20.99) and allelic association (OR = 1.73; 95% CI, 1.02 to 2.95) was observed with ABCB1 C3435T and response phenotype. The response to antiepileptics seems to be modulated by C3435T in ABCB1 or P-gp activity. At present, role of other genetic factors in treatment responsiveness in epilepsy appears limited, warranting analysis in a larger cohort.
ISSN:	0022-3859 0972-2823
DOI:	10.4103/0022-3859.138739