Stability of drug mixtures in postoperative analgesia. Estimation of their stability and plasma levels by LC-MS/MS : identification of transformation products and metabolites by LC-HRMS and LC-DAD

Abstract

The aim of this work was to determine if the multimodal analgesia by intravenous infusion of the mixture of drugs composed by dipyrone, tramadol and metoclopramide is an effective way of analgesia administration to postoperative patients. Depending on the pain level suffered by the patient after a surgical intervention, the department of Anaesthesiology, Resuscitation and Pain therapy of the General University Hospital of Castellon must evaluate two procedures of drugs administration in post-operatory analgesia. The first one is selected for patients with acute pain, and consist on a mixture of 6 g of dipyrone, 300 mg of tramadol and 30 mg of metoclopramide in 500 mL of physiological saline and infused intravenously during 24 hours. The other one, 2 g of dipyrone, 100 mg of tramadol and 10 mg of metoclopramide is dissolved in 100 mL of saline and infused for 20 minutes every 8 hours to patients with moderate pain (the template for the analgesic treatment order can be found in Figure S 1 of supplementary information). This work was divided in three sections: The first step was to develop a Liquid Chromatography coupled to tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of dipyrone, tramadol and metoclopramide in physiological saline with the purpose of performing a stability study during 24 hours of the mixture prior to intravenous administration. In this stability study, High Performance Liquid Chromatography coupled to triple quadrupole mass spectrometry (HPLC-QqQ) was used, butsupplementary information about possible transformation products was obtained from liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) and HPLC-diode-array detector (HPLCDAD). The next step was to develop and validate an analytical method by HPLC-QqQ for quantification of tramadol, metoclopramide, dipyrone and their metabolites in blood plasma of patients to make a pharmacokinetic study and compare the therapeutic effect of the two procedures of analgesia administrated to post-operatory patients. The last study goal is to find out non-reported metoclopramide metabolites to better understanding the human metabolism of that drug, since it was founded less information about metabolism of metoclopramide compared to dipyrone or tramadol. To this end, blood plasma samples prior and after post-operatory analgesia administration where analysed by LC-HRMS and compared.