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 Opportunities: Research Grants - Young Investigators Grants
• Duration: December 01, 2017 - November 30, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Adriana Maria Calvo
• Grantee: Adriana Maria Calvo
• Host Institution: Faculdade de Odontologia de Bauru (FOB). Universidade de São Paulo (USP). Bauru , SP, Brazil
• Associated 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): 20/04730-7 - Analysis of different drug extraction methods in saliva samples for LC MS / MS assays, BP.MS; 20/04734-2 - Pharmacokinetics of naproxen, celecoxib and meloxicam and the validation of the extraction methodology in saliva samples by LC MS/MS, BP.MS; 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

Abstract

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)

Scientific publications

(8)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DIONISIO, THIAGO JOSE; OLIVEIRA, GABRIELA MORAES; MORETTIN, MARINA; FARIA, FLAVIO CARDOSO; SANTOS, CARLOS FERREIRA; CALVO, ADRIANA MARIA. Simultaneous separation of naproxen and 6-O-desmethylnaproxen metabolite in saliva samples by liquid chromatography-tandem mass spectrometry: Pharmacokinetic study of naproxen alone and associated with esomeprazole. PLoS One, v. 15, n. 8, AUG 11 2020. (17/12725-0)

OLIVEIRA, GABRIELA MORAES; DIONISIO, THIAGO JOSE; SIQUEIRA-SANDRIN, VIVIANE SILVA; FERRARI, LETICIA ALVES DE LIMA; COLOMBINI-ISHIKIRIAMA, BELLA LUNA; FARIA, FLAVIO AUGUSTO CARDOSO; SANTOS, CARLOS FERREIRA; CALVO, ADRIANA MARIA. Liquid Chromatography-Tandem Mass Spectrometry Method for Detection and Quantification of Meloxicam and 5 '-Carboxymeloxicam in Oral Fluid Samples. METABOLITES, v. 13, n. 6, p. 14-pg., 2023-06-01. (17/12725-0, 22/11140-7)

SIQUEIRA SANDRIN, VIVIANE SILVA; OLIVEIRA, GABRIELA MORAES; WECKWERTH, GIOVANA MARIA; DEL HIERRO POLANCO, NELSON LEONEL; CARDOSO FARIA, FLIVIO AUGUSTO; SANTOS, CARLOS FERREIRA; CALVO, ADRIANA MARIA. Analysis of Different Methods of Extracting NSAIDs in Biological Fluid Samples for LC-MS/MS Assays: Scoping Review. METABOLITES, v. 12, n. 8, p. 18-pg., 2022-08-01. (17/12725-0, 20/04730-7)

OLIVEIRA, GABRIELA MORAES; DIONISIO, THIAGO JOSE; DEL HIERRO POLANCO, NELSON LEONEL; SIQUEIRA-SANDRIN, VIVIANE SILVA; CARDOSO FARIA, FLAVIO AUGUSTO; SANTOS, CARLOS FERREIRA; CALVO, ADRIANA MARIA. Simultaneous separation of naproxen and 6-O-desmethylnaproxen metabolite in saliva samples by liquid chromatography-tandem mass spectrometry: Pharmacokinetic study of naproxen alone and associated with esomeprazol-Results. PLoS One, v. 17, n. 12, p. 11-pg., 2022-12-01. (20/04730-7, 20/04734-2, 17/12725-0)

OLIVEIRA, GABRIELA MORAES; DIONISIO, THIAGO JOSE; FLEURY, CAMILA ASSIS; CALVO, ADRIANA MARIA; SANTOS, CARLOS FERREIRA; CARDOSO FARIA, FLAVIO AUGUSTO. Is It Safe to Use Vasoconstrictors in Association Treated with Amitriptyline or Can It Potentiate Cardiovascular Effects? In Vivo Animal Study. APPLIED SCIENCES-BASEL, v. 12, n. 23, p. 10-pg., 2022-12-01. (17/12725-0, 15/03965-2)

WECKWERTH, GIOVANA MARIA; DIONISIO, THIAGO JOSE; COSTA, YURI MARTINS; ZUPELARI-GONCALVES, PAULO; OLIVEIRA, GABRIELA MORAES; TORRES, ELZA ARAUJO; BONJARDIM, LEONARDO RIGOLDI; FARIA, FLAVIO AUGUSTO CARDOSO; CALVO, ADRIANA MARIA; MOORE, TROY; et al. Multifocal Analysis of Acute Pain After Third Molar Removal. FRONTIERS IN PHARMACOLOGY, v. 12, APR 15 2021. (17/12725-0, 18/04157-5)

BRUNA BOLANI; GABRIELA MORAES OLIVEIRA; THIAGO JOSÉ DIONÍSIO; FLAVIO AUGUSTO CARDOSO FARIA; MARIA HELENA RAPOSO FERNANDES; CARLOS FERREIRA SANTOS; ADRIANA MARIA CALVO. Pharmacogenetic and Pharmacokinetic Assays from Saliva Samples Can Guarantee Personalized Drug Prescription. Brazilian Dental Journal, v. 32, n. 1, p. 3-8, 2021-04-02. (18/02556-0, 09/17851-8, 17/12725-0)

OLIVEIRA, GABRIELA MORAES; DIONISIO, THIAGO JOSE; SIQUEIRA-SANDRIN, VIVIANE SILVA; DE LIMA FERRARI, LETICIA ALVES; BOLANI, BRUNA; PARISI, VIVIANE APARECIDA; DEL HIERRO POLANCO, NELSON LEONEL; COLOMBINI-ISHIKIRIAMA, BELLA LUNA; CARDOSO FARIA, FLAVIO AUGUSTO; SANTOS, CARLOS FERREIRA; et al. CYP2C9 Polymorphism Influence in PK/PD Model of Naproxen and 6-O-Desmethylnaproxen in Oral Fluid. METABOLITES, v. 12, n. 11, p. 12-pg., 2022-11-01. (17/12725-0)