Pharmacogenetics of non-steroidal anti-inflammatory drugs: existing problems for clinical practice

Abstract

NSAIDs are the most commonly used drugs in clinical practice for pain relief in various diseases. To date, considerable scientific material has been accumulated on the pharmacogenetics of NSAIDs and the role of genetic factors that can influence the pharmacokinetics and pharmacodynamics of drugs, changing the efficacy and toxicity profile. The most clinically significant changes in pharmacokinetics in carriers of slow alleles of CYP2C9*3 have been identified for celecoxib and flurbiprofen, which determines the need for testing and lowering of drug doses. Studies were carried out to study the role of polymorphism of the metabolizing enzymes CYP2C9, CYP2C8, UGT in the development of gastrotoxicity and gastrointestinal bleeding during application NSAIDs, as well as diclofenac’s hepatotoxicity. The association of «slow» alleles CYP2C8*3 and CYP2C9*2,*3 with the risk of gastrointestinal bleeding associated with NSAID use, which are substrates of CYP2C9 and CYP2C8, is shown. The effect of variants of alleles PTGS1 (gene COX-1) and PTGS2 (gene COX-2) on pharmacodynamics, efficacy and toxicity of NSAIDs, in particular, the severity of the analgesic effect and cardiotoxicity of the drugs, was studied. In this way, pharmacogenetic predictors of adverse effects that patients can experience, and the need for dose adjustment based on the patient’s genotype, or individualizing the choice of alternative NSAIDs to increase the effectiveness of analgesia, have been determined.

Keywords

• nsaids
• genetic polymorphism
• cyp2c9 isoform
• pharmacokinetics
• pharmacodynamics
• gastrotoxicity
• gastrointestinal bleeding
• hepatotoxicity