Background and Aims: The influence of genetic variations on drug efficacy has garnered interest in the treatment of gastrointestinal (GI) disorders, particularly gastroesophageal reflux disease (GERD). Proton pump inhibitors (PPIs), the cornerstone of GERD management, are metabolized by the cytochrome P450 enzyme CYP2C19, whose activity is variable due to genetic polymorphisms. Pharmacogenomic testing offers a novel approach to personalize PPI therapy, maximizing efficacy and minimizing adverse effects. This study aims to evaluate the role of CYP2C19 polymorphisms in PPI metabolism and explore the clinical implications of pharmacogenomic-guided therapy for GERD. Methods: A comprehensive literature review was conducted, examining clinical trials, observational studies, and meta-analyses related to CYP2C19 polymorphisms and their impact on PPI efficacy in GERD management. Sources included PubMed-indexed articles from 2000 to 2023, focusing on genetic variability, pharmacogenomic testing, and its integration into clinical practice. Data on metabolizer phenotypes, dosing strategies, and patient outcomes were synthesized to identify trends and inform recommendations. Results: CYP2C19 polymorphisms significantly influence PPI metabolism and therapeutic outcomes. Poor metabolizers (PMs) exhibit prolonged PPI exposure, enhanced acid suppression, and improved symptom control, whereas ultra-rapid metabolizers (UMs) experience suboptimal effects due to faster drug clearance. Genotype-guided dosing improves therapeutic outcomes by tailoring PPI regimens to individual metabolic profiles. Despite evidence supporting pharmacogenomic testing, barriers to implementation include cost, limited clinician education, and lack of standardized protocols. Conclusions: Pharmacogenomic testing holds promise for optimizing GERD treatment by personalizing PPI therapy based on CYP2C19 genotype. Addressing barriers to clinical implementation and expanding research to include second-generation PPIs and pediatric populations will enhance the applicability of this approach. Integrating pharmacogenomics into routine practice may reduce adverse effects and improve patient outcomes.
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