ABSTRACT
Background: Pharmacokinetics is a widely used anti-epileptic drug phenytoin, which exhibits noticeable inter-individual variations in efficacy. Genetic factors, such as MDR1 gene polymorphism may play a crucial role in drug response
Objective: To investigate the influence of MDR1 variant genotypes on Phenytoin Pharmacokinetics in epileptic patients
Design: A Case-Control Genetic Study
Setting: College of Medicine and Pharmacy, King Khalid University, Abha, Saudi Arabia
Method: Twenty-five epileptic patients non-responders to phenytoin monotherapy and 25 epileptic patients' responders to phenytoin monotherapy were recruited. DNA was isolated by conventional phenol-chloroform method. MDR1 [3435C>T] gene polymorphism was assessed using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphisms [PCR-RFLP] method. Allelic and genotypic frequency were calculated. Reversed-phase High-Performance Liquid Chromatography [HPLC] method was used to determine the plasma levels of Phenytoin drug. PK Solutions was used for non-compartmental analysis to estimate the pharmacokinetic parameters
Result: The MDR1 [3435C>T] polymorphism was found to be in Hardy-Weinberg equilibrium and displayed significant allelic and genotypic association between non-responders and responders to phenytoin [P<0.01]. The finding of pharmacokinetics analysis demonstrated that longer halflife [t1/2 = 33.26 hours] and less clearance rate [CL = 0.42 L/hour] in the homozygous variant group compared to wild-type genotype group [t 1/2 = 19.2hrs, CL = 0.8 L/hour]
Conclusion: The finding suggests that the genetic polymorphism in the C3435T location of MDR1 gene might determine pharmacokinetics variability of phenytoin drug. Therefore, pharmacokinetics parameters along with genotyping of MDR1 [C3435T] genotype might be valuable in the perspective of personalized medicine in epileptic patients