Simultaneous separation of naproxen and its metabolite 6-Odesmethylnaproxen in saliva by LC MS/MS: pharmacokinetic study of naproxen and its association with esomeprazole

Author(s)

Nelson Leonel Del Hierro Polanco

• Document type: Master's Dissertation
• Press: Bauru.
• Institution: Universidade de São Paulo (USP). Faculdade de Odontologia de Bauru (FOB/SDB)
• Defense date: 2022-05-19

Examining board members

Adriana Maria Calvo; Michele Garcia Usó; Bella Luna Colombini Ishikiriama; Maria Noel Marzano Rodrigues

• Advisor: Adriana Maria Calvo

Abstract

Naproxen is a non-steroidal anti-inflammatory drug widely used in dentistry and medicine to control the signs and symptoms of inflammation. Although this drug has a slower absorption when associated with esomeprazole, the combination of both drugs has been studied and shown good results for the control of acute pain. In order to better understand the absorption, distribution and metabolism of this drug and its association with esomeprazole, a pharmacokinetic analysis of naproxen and the metabolite 6-O-desmethylnaproxen was proposed in saliva samples using liquid chromatography coupled to a mass spectrometer (LC MS/MS) and developed and validated a fast, selective and sensitive method for the simultaneous determination of both analytes in this fluid. Sequential saliva samples from 12 patients were analyzed before and after ingestion of a naproxen tablet and a naproxen tablet plus esomeprazole. A liquid-liquid extraction methodology (LLE) was used for the LC MS/MS analysis. The total analysis time was 5 minutes. The combination of naproxen and esomeprazole took longer to reach maximum concentration (Tmax 32.6 ± 62.1h for naproxen and 86.1 ± 95.2h* for naproxen with esomeprazole, p<0.05). Elimination values were similar for naproxen and its metabolite, in both presentations Kel 0.1 ± 0.1 1/h and 0.1 ± 0.1 1/h (naproxen) and Kel 1.8 ± 2.1 1/ h and 0.7 ± 0.7 1/h (naproxen + esomeprazole). The association of naproxen and esomeprazole showed increased values of the area under the curve (490.5 ± 771.7* h*ng/mL associated with esomeprazole and 105.7 ± 185.7 h*ng/mL naproxen alone, p<0.05) in drug concentration relative to naproxen alone. Decreased values in total clearance were also observed when naproxen is associated with esomeprazole (4.9 ± 4.8* g/h with esomeprazole and 15.4 ± 9.1 g/h with naproxen alone, p<0.05). Naproxen and 6-Odesmethylnaproxen in saliva samples could be quantified using LC-MS/MS and this methodology proved to be a fast, sensitive, exact and selective alternative for each drug and allowed the analysis of pharmacokinetic parameters efficiently. (AU)

• FAPESP's process: 20/04734-2 - Pharmacokinetics of naproxen, celecoxib and meloxicam and the validation of the extraction methodology in saliva samples by LC MS/MS
• Grantee: Nelson Leonel Del Hierro Polanco
• Support Opportunities: Scholarships in Brazil - Master