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

Abstract

BACKGROUND AND OBJECTIVE:

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.

MATERIALS AND METHODS:

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).

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: S R Taur, N B Kulkarni, P P Gandhe, B K Thelma, S H Ravat, N J Gogtay, U M Thatte
• Journal: Journal of postgraduate medicine (J Postgrad Med) 2014 Jul-Sep Vol. 60 Issue 3 Pg. 265-9 ISSN: 0972-2823 [Electronic] India
• PMID: 25121365 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter 1
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Anticonvulsants
• Carbamazepine
• Cytochrome P-450 CYP2C9
• Cytochrome P-450 CYP2C19

Topics

• ATP Binding Cassette Transporter 1 (genetics)
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• Adolescent
• Adult
• Aged
• Anticonvulsants (administration & dosage, pharmacology)
• Carbamazepine (administration & dosage, pharmacology)
• Cross-Sectional Studies
• Cytochrome P-450 CYP2C19 (genetics)
• Cytochrome P-450 CYP2C9 (genetics)
• Drug Resistance (genetics)
• Epilepsy (drug therapy, genetics, metabolism)
• Female
• Gene Frequency
• Genetic Variation
• Genotype
• Humans
• Logistic Models
• Male
• Middle Aged
• Pharmacogenetics
• Polymorphism, Restriction Fragment Length
• Young Adult