Pharmacogenetic and Pharmacokinetics of Naproxen and Associated Naproxen-esomeprazole
Condition: Poor Metabolizer Due to Cytochrome P450 CYP2C9 Variant; Poor Metabolizer Due to Cytochrome p450 CYP2C19 Variant
Study type: Interventional
Phase: Phase 4

Summary: 
      The family of cytochrome P450 (CYP) is the most important drug metabolizing enzymes which
      contributes to the metabolism of a large proportion of drugs in humans. Some CYP450 enzymes
      reduce or alter the pharmacodynamic activity of many drugs and are involved in oxidative
      metabolism and elimination of many drugs commonly used by the population. Polymorphisms in
      CYP2C8 and CYP2C9 are common in different populations around the world and genetic variations
      in these alleles can cause decreased enzyme activity to nonsteroidal anti-inflammatory drugs
      (NSAIDs) such as celecoxib, diclofenac, ibuprofen, indomethacin, lornoxicam, meloxicam,
      valdecoxib, piroxicam, tenoxicam and naproxen. This compromise the bioavailability of the
      drug can alter the pharmacokinetics of these drugs and patients with mutations in these genes
      can exhibit increased plasma concentrations of values and areas under the curve (AUC), in
      addition to decreased clearance of drugs. Associations between NSAIDs and gastric protectors
      or proton pump inhibitors (PPIs) have become common nowadays, especially in patients who make
      chronic use of these drugs. Naproxen associated to esomeprazole, a proton pump inhibitor
      (PPI), was launched in the market recently and its application in acute pain is not yet
      elucidated. Esomeprazole suffers strong influence of CYP2C19 (hepatic drug-metabolizing
      enzyme that degrades PPIs). In patients with high enzyme activity of the CYP2C19, the drug
      can suffer high enzymatic degradation, and its diminished effect. Moreover, in patients with
      low enzyme CYP2C19 activity, the effect of acid inhibition by PPIs can be very strong.
    

Detailed description: 
      The genotype presented by the patient in relation to CYP2C8, 2C9 and 2C19 could influence the
      absorption and metabolism of these NSAIDs with or without the gastric protectors, and may
      differ from anti-inflammatory action and side effects. In this proposal, 20 volunteers will
      be genotyped and phenotyped for these haplotypes of cytochrome P450. For analysis of the
      proposed genes, saliva will be collected as a source of genomic DNA. For molecular analysis
      will be performed polymerase chain reaction (PCR) assays are used produced and validated by
      Applied Biosystems®. For pharmacokinetics will be collected saliva samples at various times
      after ingestion of a tablet of naproxen (500 mg) or naproxen associated to esomeprazole (500
      + 20 mg), using mass spectrometry for analysis of drug concentrations in the samples. The
      results will be described with a 0.05 significance level.
    

Intervention name(s): Naproxen; Naproxen-esomeprazole
Intervention type(s): Drug; Drug
Intervention description(s): 20 phenotyped for CYP2C9 and CYP2C19 (by PCR) and for the pharmacokinetics of naproxen, saliva samples will be collected of these patients at different times after ingestion of a tablet of naproxen (500mg) (before, 0,25; 0,5; 0,75; 1; 1,5; 2; 3; 4; 5; 6; 8; 11; 24; 48; 72 e 96 hours after ingestion).; 20 phenotyped for CYP2C9 and CYP2C19 (by PCR) and for the pharmacokinetics of naproxen-esomeprazole, saliva samples will be collected of these patients at different times after ingestion of a tablet of naproxen-esomeprazole (500mg+20mg) (after one month of the first collection) (before, 0,25; 0,5; 0,75; 1; 1,5; 2; 3; 4; 5; 6; 8; 11; 24; 48; 72 e 96 hours after ingestion).
Other intervention name(s): CYP2C9; CYP2C9; CYP2C19
Intervention MeSH terms: Naproxen; Esomeprazole
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Naproxen; Association of naproxen-esomeprazole; High pressure liquid chromatography; Cytochrome P450