Impact of Genetic Polymorphisms on Phenytoin Pharmacokinetics and Clinical Outcomes in the Middle East and North Africa Region

BACKGROUND Genetic polymorphisms are known to influence outcomes with phenytoin yet effects in the Middle East and North Africa region are poorly understood. OBJECTIVES The objective of this systematic review was to evaluate the impact of genetic polymorphisms on phenytoin pharmacokinetics and clinical outcomes in populations originating from the Middle East and North Africa region, and to characterize genotypic and allelic frequencies within the region for genetic polymorphisms assessed. METHODS MEDLINE (1946-3 May, 2017), EMBASE (1974-3 May, 2017), Pharmacogenomics Knowledge Base, and Public Health Genomics Knowledge Base online databases were searched. Studies were included if genotyping and analyses of phenytoin pharmacokinetics were performed in patients of the Middle East and North Africa region. Study quality was assessed using a National Institutes of Health assessment tool. A secondary search identified studies reporting genotypic and allelic frequencies of assessed genetic polymorphisms within the Middle East and North Africa region. RESULTS Five studies met the inclusion criteria. CYP2C9, CYP2C19, and multidrug resistance protein 1 C3435T variants were evaluated. While CYP2C9*2 and *3 variants significantly reduced phenytoin metabolism, the impacts of CYP2C19*2 and *3 variants were unclear. The multidrug resistance protein 1 CC genotype was associated with drug-resistant epilepsy, but reported impacts on phenytoin pharmacokinetics were conflicting. Appreciable variability in minor allele frequencies existed both between and within countries of the Middle East and North Africa region. CONCLUSIONS CYP2C9 decrease-of-function alleles altered phenytoin pharmacokinetics in patients originating from the Middle East and North Africa region. The impacts of CYP2C19 and multidrug resistance protein 1 C3435T variants on phenytoin pharmacokinetic and clinical outcomes are unclear and require further investigation. Future research should focus on the clinical outcomes associated with phenytoin therapy. PROSPERO 2017: CRD42017057850.