[Drug-drug interaction in pharmacogenetics and pharmacogenomics]

Drug metabolism and excretion is composed of four steps: Absorption, distribution, metabolism and excretion. The four steps are often abbreviated as ADME. Drug-drug interaction may occur at each step of ADME. Reported examples of drug-drug interaction occur mainly at the level of "drug metabolizing enzymes(DME)". The mechanisms of drug-drug interaction are: 1) Competitive inhibition of DME, 2) Destruction or irreversible inhibition of DME, 3) Induction of DME. Co-administration of 5-fluorouracil and sorivudine resulted in severe gastrointestinal and bone marrow toxicities. The toxicity is due to irreversible inhibition of dihydropyrimidine dehydrogenase by a sorivudine metabolite, which plays a role in detoxification of 5-fluorouracil. However, there is an example of beneficial drug-drug interaction, where proton pump inhibitor, omeprazole, antibiotics, amoxicillin and clarithromycin, are co-administered for eradication of Helicobacter pylori. Omeprazole is metabolized by CYP2C19 and CYP3A4. In poor metabolizers of omeprazole, a higher area under the drug concentration curve(AUC) and higher efficacy are achieved as compared to extensive metabolizers of omeprazole. In this regimen, co-administration of clarithromycin which is metabolized by CYP3A4 effectively raises the AUC of omeprazole. Thus, this drug combination results in a beneficial drug-drug interaction.