- Discuss pharmacogenomics as it relates to gastroenterology with the focus on H. pylori infection.
- Outline the effects of genetic polymorphism on proton pump inhibitors and their efficacy in H. pylori.
- Illustrate how pharmacogenomics can be used to tailor therapy with proton pump inhibitors.
Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprazole, are now clinically used as the potent gastric acid inhibitors. They are derivatives of benzimidazole. They are absorbed in the small intestine and reach, via systemic circulation, the gastric parietal cells, where they bind to the proton pump (H+/K+-ATPase) irreversibly and disturb the function of proton pump, thereby resulting in a potent acid inhibition.1 The major indications of PPIs are acid-related diseases, such as peptic ulcer, gastroesophageal reflux diseases (GERD), and Zollinger–Ellison syndrome.2–6 PPIs are also used for the eradication of H. pylori with antimicrobial agents.7–9
PPIs undergo the hepatic metabolism by the cytochrome P450 (CYP) system. The principal enzyme involved in the metabolism of PPIs is CYP2C19. CYP3A4 is also involved in PPI metabolism.10–14 For example, omeprazole, a representative and first clinically available PPI, is mainly metabolized by CYP2C19 to 5-hydroxyomeprazole, which is metabolized by CYP3A4 to 5-hydroxyomeprazole sulfone. Omeprazole is partially first metabolized by CYP3A4 to omeprazole sulfone, which is metabolized by CYP2C19 to 5-hydroxyomeprazole sulfone (Figure 17A–1). There are interindividual differences in the activity of CYP2C19. Recent reports have revealed that pharmacokinetics and pharmacodynamics of PPIs are affected by the CYP2C19 polymorphism.
Metabolism of omeprazole (OME) in relation to cytochrome P450 (CYP) isoenzymes. Weight of arrows indicates the relative contribution of different enzyme pathways. OME is mainly metabolized by CYP2C19 to 5-hydroxyomeprazole (5-OH-OME), which is then metabolized to 5-hydroxyomeprazole sulfone (5-OH-OME-SFN). OME is also metabolized by CYP3A4 to omeprazole sulfone (OME-SFN), which is then metabolized by CYP2C19 to 5-OH-OME-SFN.
Polymorphism of Cytochrome P450 Enzymes
There are more than 20 kinds of CYP enzymes in the liver. These enzymes hydrolyze a variety of drugs. Among CYP enzymes, CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 are important in the metabolism of drugs in humans.15 Most of CYP450 enzymes show a genetic polymorphism associated with their enzyme activities (http://www.imm.ki.se/CYPalleles/default.htm). Plasma concentrations and effects of drugs metabolized by these enzymes differ among different individuals with their different enzyme activities genetically determined.
Genetic Differences in the Main PPI-Metabolizing Enzyme, CYP2C19
PPIs are mainly metabolized by CYP2C19 (Figure 17A–1). There are interindividual differences in the activity of this enzyme, which was first characterized by the racemic antiepileptic agent, mephenytoin, of which the S-enantiomer undergoes hydroxylation through CYP2C19.10,15,16 The polymorphism of this enzyme is classified into the three genotype groups: ...