CYP2C19 Gene Profiling as a Tool for Personalized Stress Ulcer Prophylaxis With Proton Pump Inhibitors in Critically Ill Patients - Recommendations Proposal

Abstract

To this date, there are no recommendations for personalized stress ulcer prophylaxis (SUP) in critical care that would take the patient's individual genetic predispositions into account. Of drugs used for this purpose, proton pump inhibitors (PPIs) are the first-choice drugs in intensive care unit patients. The degradation of proton pump inhibitors is mediated by cytochrome P450 (CYP) enzymes; in particular, CYP2C19 and, to a lesser extent, CYP3A4 are involved. Expression and metabolic activity of, namely in, CYP2C19 is significantly affected by single nucleotide polymorphisms, the drug metabolization rate varies greatly from ultrarapid to poor and likely influences the optimal dosage. As these CYP2C19 predictive phenotypes via CYP2C19 haplogenotypes (rs12248560/rs4244285) can be relatively easily determined using the current standard equipment of hospital laboratories, we prepared a set of recommendations for personalized PPI-based stress ulcer prophylaxis taking into account the patient's CYP2C19 predictive phenotype determined in this way. These recommendations are valid, in particular, for European, American and African populations, because these populations have the high representations of the CYP2C19^*17 allele associated with the overexpression of the CYP2C19 gene and ultrarapid degradation of PPIs. We propose the CYP2C19 gene profiling as a tool for personalized SUP with PPI in critically ill patients.

Keywords: critical care; gene polymorphism; personalized therapy; pharmacogenetics; poor metabolizer; proton pump inhibitors; stress ulcer prophylaxis; ultra-rapid metabolizer.

Figure 1

Distribution of the CYP2C19 haplogenotype frequencies affecting proton pump inhibitors (PPI) metabolization in various populations. PM, poor metabolizer; IM, intermediate metabolizer; AM, ambivalent metabolizer; EM, extensive metabolizer; RM, rapid metabolizer; UM, ultrarapid metabolizer; CYP, cytochrome P450. The dotted line divides the figure into two populations in which haplogenotypes were determined experimentally (29, 30), and nine populations in which the haplogenotypes were calculated from a database containing haplotype (diplotype) frequencies estimated using the equation describing Hardy Weinberg equilibrium based on reported allele frequencies (22). Six CYP2C19 haplotypes/predictive phenotypes results from combination of two CYP2C19 polymorphisms (rs12248560 for detection of allele CYP2C19*17 / rs4244285 for detection of allele CYP2C19*2). ^#CYP2C19 *1*17/*2*2, *17*17/*2*2, and *17*17/*1*2 haplogenotypes with unknown phenotype are merged with AMs.