Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC–MS/MS

Haage, Pernilla; Kronstrand, Robert; Carlsson, Björn; Kugelberg, Fredrik C.; Josefsson, Martin

doi:10.1016/j.jpba.2015.11.012

Cited by 14 publications

(8 citation statements)

References 25 publications

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“…The enantioselective analysis of tramadol, ODT, NDT, and NODT in whole blood was performed at the National Board of Forensic Medicine in Linköping, Sweden, using a validated LC‐MS/MS‐method that has been described in detail previously . In brief, blood samples of 0.5 g were fortified with an internal standard consisting of tramadol‐ 13 C‐D 3 and O ‐desmethyl‐cis‐tramadol‐D 6 , followed by liquid–liquid extraction at pH 11.…”

Section: Methodsmentioning

confidence: 99%

“…The enantioselective analysis of tramadol, ODT, NDT, and NODT in whole blood was performed at the National Board of Forensic Medicine in Linköping, Sweden, using a validated LC-MS/MS-method that has been described in detail previously. 14 (two standard deviations). Long-term stability tests at a low (1 ng/g) and a high (200 ng/g) enantiomer concentration were performed in −80°C up to 24 months.…”

Section: Pharmacokinetic Assessmentsmentioning

confidence: 99%

“…The overall aim of the present study was therefore to obtain such metabolic profiles in healthy volunteers receiving a single, therapeutic dose of tramadol. The enantioselective method needed for conducting such a study has previously been developed and validated . Specifically, the following research questions and hypotheses were posted: Can interindividual differences in enantioselective metabolic profiles be explained by CYP2D6, CYP2B6 , and/or CYP3A4 genotype?…”

Section: Introductionmentioning

confidence: 99%

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Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype

Haage

Kronstrand

Josefsson

et al. 2018

Pharmacology Res & Perspec

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Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)‐ and (−)‐enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O‐desmethyltramadol, N‐desmethyltramadol, and N,O‐didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained. Nineteen healthy volunteers were orally administered either 50 or 100 mg tramadol, whereupon blood samples were drawn at 17 occasions. Enantiomer concentrations in whole blood were measured by LC‐MS/MS and the CYP2D6,CYP2B6 and CYP3A4 genotype were determined, using the xTAG CYP2D6 Kit, pyrosequencing and real‐time PCR, respectively. A positive correlation between the (+)/(−)‐enantiomer ratio and time following drug administration was shown for all four enantiomer pairs. The largest increase in enantiomer ratio was observed for N‐desmethyltramadol in CYP2D6 extensive and intermediate metabolizers, rising from about two to almost seven during 24 hours following drug intake. CYP2D6 poor metabolizers showed metabolic profiles markedly different from the ones of intermediate and extensive metabolizers, with large area under the concentration curves (AUCs) of the N‐desmethyltramadol enantiomers and low corresponding values of the O‐desmethyltramadol and N,O‐didesmethyltramadol enantiomers, especially of the (+)‐enantiomers. Homozygosity of CYP2B6 *5 and *6 indicated a reduced enzyme function, although further studies are required to confirm it. In conclusion, the increase in enantiomer ratios over time might possibly be used to distinguish a recent tramadol intake from a past one. It also implies that, even though (+)‐O‐desmethyltramadol is regarded the enantiomer most potent in causing adverse effects, one should not investigate the (+)/(−)‐enantiomer ratio of O‐desmethyltramadol in relation to side effects without consideration for the time that has passed since drug intake.

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Section: Methodsmentioning

confidence: 99%

“…The enantioselective analysis of tramadol, ODT, NDT, and NODT in whole blood was performed at the National Board of Forensic Medicine in Linköping, Sweden, using a validated LC-MS/MS-method that has been described in detail previously. 14 (two standard deviations). Long-term stability tests at a low (1 ng/g) and a high (200 ng/g) enantiomer concentration were performed in −80°C up to 24 months.…”

Section: Pharmacokinetic Assessmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype

Haage

Kronstrand

Josefsson

et al. 2018

Pharmacology Res & Perspec

Self Cite

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“…Numerous analytical methods have been described for the quantitative determination of MEP, TRAM or dextropropoxyphene, alone or with their metabolites, in plasma samples. Gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) are the main techniques used for most of these methods.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous quantitation of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma using solid‐phase extraction and gas chromatography/mass spectrometry: Method validation and application to cardiovascular safety of therapeutic doses

Fernández

Olivera

Keller

et al. 2017

Rapid Comm Mass Spectrometry

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Rationale Several opioid analgesics have been related to the prolongation of cardiac repolarization, a condition which can be fatal. In order to establish a correct estimation of the risk/benefit balance of therapeutic doses of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene, it was necessary to develop an analytical method to determinate plasma concentrations of these opioids. Methods Here we describe a method which incorporates strong alkaline treatment to obtain norpropoxyphene amide followed by a one‐elution step solid‐phase extraction, and without further derivatization. Separation and quantification were achieved by gas chromatography/electron ionization mass spectrometry (GC/EI‐MS) in selected‐ion monitoring mode. Quantification was performed with 500 μL of plasma by the addition of deuterated analogues as internal standards. Results The proposed method has been validated in the linearity range of 25–1000 ng/mL for all the analytes, with correlation coefficients higher than 0.990. The lower limit of quantification was 25 ng/mL. The intra‐ and inter‐day precision, calculated in terms of relative standard deviation, were 2.0–12.0% and 6.0–15.0%, respectively. The accuracy, in terms of relative error, was within a ± 10% interval. The absolute recovery and extraction efficiency ranged from 81.0 to 111.0% and 81.0 to 105.0%, respectively. Conclusions A GC/MS method for the rapid and simultaneous determination of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma was developed, optimized and validated. This procedure was shown to be sensitive and specific using small specimen amounts, suitable for application in routine analysis for forensic purposes and therapeutic monitoring. To our knowledge, this is the first full validation of the simultaneous determination of these opioids and their metabolites in plasma samples.

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“…Several spectrophotometry [30], chemiluminescence [31], colorimetric [32], spectrophotometric [33], chromatography [34], capillary electrophoresis [35], and electrochemical methods [36][37][38] have been published for the evaluation of tramadol in pharmaceutical formulations. Some cases of suspected interaction between tramadol and warfarin have been published [39][40][41][42].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of conductive polymeric ionic liquid/Ni nanocomposite and its application to construct a nanostructure based electrochemical sensor for determination of warfarin in the presence of tramadol

Molaakbari

Mostafavi

Beitollahi

et al. 2017

Talanta

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Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC–MS/MS

Cited by 14 publications

References 25 publications

Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype

Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype

Simultaneous quantitation of meperidine, normeperidine, tramadol, propoxyphene and norpropoxyphene in human plasma using solid‐phase extraction and gas chromatography/mass spectrometry: Method validation and application to cardiovascular safety of therapeutic doses

Synthesis of conductive polymeric ionic liquid/Ni nanocomposite and its application to construct a nanostructure based electrochemical sensor for determination of warfarin in the presence of tramadol

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