Abstract
Background: Epilepsy is a common chronic neurological condition that is characterized by recurrent unprovoked seizures. A synonymous C to T variant at position 3435 (3435C N T) is one common polymorphism of the multidrug resistant 1 (MDR1) gene, which encodes the major transmembrane efflux transporter P-glycoprotein and form an important class of proteins for regulating pharmacokinetics. Phenytoin, a widely used anti-epileptic drug, exhibits marked inter-individual variation in Pharmacokinetics and attributed to genetic factors such as MDR1 polymorphism. Objective: The present study was undertaken to investigate the influence of MDR1 variant genotypes on Phenytoin Pharmacokinetics in the epileptic patients from Saudi Arabia. Material andmethods: 25 epileptic individuals with non-responders to phenytoin monotherapy and 25 epileptic subjects with responders to phenytoin monotherapy were recruited after getting their informed consent and genotyped for MDR1 (3435C N T) polymorphisms by Polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP Method). Allele frequencies were derived from genotypic data Phenytoin plasma levels were analyzed by reverse phase HPLC method and Pharmacokinetic parameters were estimated by non-compartmental analysis using PK solutions software. Results: The MDR1 (3435C N T) polymorphism was seen to be in Hardy–Weinberg equilibrium and showed significant allelic association and genotypic association between non responders and responders to phenytoin (P b 0.01). The pharmacokinetics parameters in homozygous mutant group showed longer half-life (t1/ 2= 33.26 hrs) and less clearance rate (CL=0.42 L/hr) when compared to wild type group (t 1/2=19.2 hrs, CL=0.8 L/hr). Conclusion: Our finding suggest that the MDR1 genetic polymorphism influences Phenytoin Pharmacokinetics. So the therapeutic outcome of MDR1 (C3435T) genotype together with pharmacokinetic measurements might be useful in the context of improving the individualized efficacy of therapy in non-responders to phenytoin.
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