Validated determination method of tramadol and its desmethylates in human plasma using an isocratic LC-MS/MS and its clinical application to patients with cancer pain or non-cancer pain

Abstract

BackgroundThis study aimed to develop a simultaneous determination method for tramadol and its desmethylates in human plasma using isocratic liquid chromatography coupled to tandem mass spectrometry and to validate it for pharmacokinetic evaluation in patients with cancer pain or non-cancer pain.MethodsThe pretreatments for human plasma involved protein precipitation using acetonitrile and methanol under basic conditions. Tramadol, O-desmethylate, N-desmethylate, and N,O-didesmethylate were separated on an octadecylsilyl column filled with 3-μm particles using isocratic mixture of methanol and 0.15 % formic acid in water (35:65, v/v). The mass spectrometer was run in positive ion multiple reaction monitoring mode. This method was applied to the determination of plasma samples in patients treated with oral tramadol.ResultsThe chromatographic total run time was 10 min. The calibration curves in human plasma of tramadol, O-desmethylate, N-desmethylate, and N,O-didesmethylate were linear over the concentration ranges of 12.5–1600, 2.5–320, 2.5–320, and 2.5–320 ng/mL, respectively. The lower limits of quantitation of tramadol and its desmethylates in human plasma were 12.5 and 2.5 ng/mL. Their extraction recoveries were 85.5–106.3 %. The intra-day and inter-day precisions and accuracies were 1.6–10.2 % and 89.2–106.2 % for all analytes. The plasma concentration ranges of tramadol, O-desmethylate, N-desmethylate, and N,O-didesmethylate were 18.2–564, 11.8–137, 4.9–250, and 6.1–147 ng/mL in cancer patients, and 32.8–670, 7.0–84.8, 5.1–317, and 6.7–85.2 ng/mL, respectively, in non-cancer patients.ConclusionsThe present method with acceptable analytical performance can be helpful for evaluating the pharmacokinetics of oral tramadol, including the determination of its desmethylates, for patients with cancer pain or non-cancer pain in clinical settings.

Opioid‐induced inhibition of the human 5‐HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome

“…Trough concentrations at steady state at median oral daily doses of 112.5 mg divided into three doses (Tanaka et al, ).…”

Pharmacokinetics and Pharmacodynamics Evaluation of Tramadol in Thermoreversible Gels

“…Also, we decided to use “large experimental animal models” to observe extensive whole-body pharmacokinetics in a context comparable to patient physiology [ 15 , 16 ]. In our study, we also evaluated M1, the main TR metabolite, levels and its PK parameters since it has about 300-fold higher affinity for the μ receptor than TR [ 4 ].…”

“…Tramadol (TR) is an opioid analgesic widely used to treat moderate, severe, and chronic pain, such as oncologic and postoperatory pain [ 1 , 2 ]. It acts as an opioid μ 1 receptor agonist and monoamine reuptake inhibitor and as a target for some protein coupled receptor and ligand-gated ion channels [ 3 , 4 ]. The common adverse effects of tramadol are somnolence, seizures, nausea, and vomiting [ 4 ].…”

“…It acts as an opioid μ 1 receptor agonist and monoamine reuptake inhibitor and as a target for some protein coupled receptor and ligand-gated ion channels [ 3 , 4 ]. The common adverse effects of tramadol are somnolence, seizures, nausea, and vomiting [ 4 ]. TR usually evokes a low incidence of adverse effects when compared to classical opioids, such as morphine and fentanyl [ 5 ].…”

Development of a novel LC–MS/MS method for detection and quantification of tramadol hydrochloride in presence of some mislabeled drugs: Application to counterfeit study

“…A literature survey revealed that several methods have been reported for the determination of TRM either alone or in the presence of other co‐formulated materials. These include spectrophotometric (Abdellatef, ; Amin, Adawy, Ali, & El‐Shahatt, ; Dhumal, Bhusari, Ghante, & Jain, ; Glavanović, Glavanović, & Tomišić, ; Lakshmi, Ravisankar, Kumar, & Babu, ; Thomas & Sankar, ), spectrofluorimetric (Abdellatef, El‐Henawee, El‐Sayed, & Ayad, ; Smith, Manavalan, Kannan, & Rajendiran, ), chromatographic (Baconi, Stan, Abdul Jalil Ebrahim, Tuchila, & Balalau, ; Batool, Ahmed, & Rasheed, ; Desai, Captain, & Kamdar, ; Dhumal, Bhusari, Patra, Thareja, & Jain, ; Karunakaran, Navaneethan, & Elango, ; Kiarostami, Rouini, Mohammadian, Lavasani, & Ghazaghi, ; Ravisankar, Sridevi, & Kumari, ; Solomon, Anand, Shukla, Sivakumar, & Venkatnarayanan, ), electrochemical (Chitravathi & Munichandraiah, ; Deiminiat, Rounaghi, & Arbab‐Zavar, ; Fakhari, Sahragard, Ahmar, & Tabani, ; Ganjali, Razavi, Faridbod, Riahi, & Norouzi, ; Madrakian, Alizadeh, Bahram, & Afkhami, ) and electrophoresis (Cunha, Ribeiro, Muñoz, & Richter, ) methods in addition to the hyphenated methods where the chromatographic separations are coupled with the detection (El‐Sayed, Mohamed, Nasser, Button, & Holt, ; Haage, Kronstrand, Carlsson, Kugelberg, & Josefsson, ; Liu, Wang, Yu, Dong, & Yue, ; Tambe, Deodhar, & Prakya, ; Tanaka, Naito, Mino, & Kawakami, ; Yilmaz & Erdem, ). Thus, the aim of the present study was to develop a highly sensitive, rapid and accurate LC–MS/MS method for simultaneous quantitation of TRM and some expected co‐formulated compounds.…”