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Model of pharmakinetics/pharmacodynamics (PK/PD) on the influence of P450 genetic polymorphism (CYP2C9) of non-steroidal anti-inflammatory drugs and main metabolics from saliva samples through LCMS/MS and its role on prescription personalization

Grant number: 17/12725-0
Support type:Research Grants - Young Investigators Grants
Duration: December 01, 2017 - November 30, 2021
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Adriana Maria Calvo
Grantee:Adriana Maria Calvo
Home Institution: Faculdade de Odontologia de Bauru (FOB). Universidade de São Paulo (USP). Bauru , SP, Brazil
Assoc. researchers:Carlos Ferreira dos Santos
Associated grant(s):17/26387-0 - Multi-user equipment approved in grant 2017/12725-0 - mass spectrometry system coupled to ultra high efficiency liquid chromatography UHPLC, brand Shimadzu, AP.EMU
Associated scholarship(s):19/05477-6 - PK/PD study after infiltration of lidocaine with or without epinephrine in saliva samples by LC-MS/MS, BP.IC
18/02556-0 - Study of Cytochrome P450 (CYP2C9) POLYMORPHYMS for pharmacogenetic tests, BP.IC
17/24893-5 - Pharmacokinetic/pharmacodynamic (PK/PD) model on the influence of genetic polymorphism of Cytochrome P450 (CYP 2C9) of nonsteroidal anti-inflammatory and major metabolites from saliva samples by LCMS / MS and its role in the prescription customization, BP.JP


Individual responses to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are influenced by a combination of pharmacokinetic and pharmacodynamic factors (PK/PD) that may undergo a regulatory influence on some genetic factors, and this is the way to customize prescriptions today, with satisfactory effectiveness and minimal side effects. Genetic polymorphisms for the efficacy of inflammatory signal control and NSAID toxicity have not yet been fully elucidated. For our model of inflammation study, some physiological options are well established in the study of the PK/PD model. The synthesis of Prostaglandin E2 (PGE2) is modulated by the enzyme cyclooxygenase-2 (COX-2) and changes in PGE2 can be used to quantify the inhibition of COX-2 after NSAID administration, which is our principal aim of investigation for the PK/PD ratios regarding COX-2 inhibition according to the NSAIDs studied and the relation to the CYP2C9 polymorphism of the research volunteers. The use of saliva samples in pharmacokinetic studies has been successfully studied. Due to the lower cost, greater patient compliance, being a non-invasive method, with no risk of contamination, saliva samples are simpler to collect than plasma, considering the multiple collections required in pharmacokinetic studies. There are few reports of presence and detection of PGE2 in saliva, which motivated the accomplishment of this stage of research associated with the previous positive results that we obtained in the detection of drug concentrations and metabolites in this fluid for PK studies. The objective of the present research is to nucleate a new line of research at FOB/USP in PK/PD associated with pharmacogenetics with the use of saliva samples for reference NSAIDs and their respective main metabolites, being naproxen (6-0-dimethylnaproxene), Meloxicam (5'-carboximeloxicam) and celecoxib (hydroxycelecoxib). We will select 15 non-mutated homozygous volunteers and 15 volunteers mutated for CYP2C9 who will perform collections in three different periods. For the determination of the genotype of the volunteers, PCR will be used in saliva samples. The saliva collections (4 mL) will be: before and 0.25; 0.5; 0.75; 1; 1.5; 2; 3; 4; 5; 6; 8; 11; 24; 48; 72 and 96 h after the ingestion of each drug. For the analysis of PGE2 the samples of 'before' and at the moment of maximum concentration of the drug analyzed in the PK assays will be used. Plasma concentrations of the drugs, their main metabolites and PGE2 will be determined by liquid chromatography associated with the mass spectrometer (LC MS/MS). The methodology will be valid according to ANVISA standards. (AU)