Analysis of rocuronium in human plasma by liquid chromatography–tandem mass spectrometry with application in clinical pharmacokinetics

Moraes, Natália Valadares de; Lauretti, Gabriela Rocha; Filgueira, Gabriela Campos de Oliveira; Lopes, Bruno Carvalho Portes; Lanchote, Vera Lúcia

doi:10.1016/j.jpba.2013.11.032

Cited by 7 publications

(6 citation statements)

References 20 publications

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“…[12] Opening of the morpholine ring was also seen in a study dealing with a GLS4 metabolite. [13] The MS 2 mass spectrum of intact Roc was dominated by m/z 487, which has been previously observed by others, [14][15][16] without providing detailed dissociation patterns. The selected reaction monitoring (SRM) transition m/z 529 → 487 was used for sensitive quantification of Roc in human plasma [14] and whole blood and tissues.…”

Section: Resultssupporting

confidence: 65%

“…[13] The MS 2 mass spectrum of intact Roc was dominated by m/z 487, which has been previously observed by others, [14][15][16] without providing detailed dissociation patterns. The selected reaction monitoring (SRM) transition m/z 529 → 487 was used for sensitive quantification of Roc in human plasma [14] and whole blood and tissues. [15] Loss of 42 Da was observed using a single quadrupole instrument, which was attributed to deacetylation.…”

Section: Resultssupporting

confidence: 65%

“…Based on the previous degradation reactions seen for other morpholine ring‐containing drugs, we hypothesize that Roc → X transformation under forced degradation conditions occurred at the morpholine moiety of the molecule. To prove this hypothesis, X was also analyzed by CID and the results compared to Roc and E. The first dissociation step in MS 2 was cleavage of propenyl (C 3 H 6 ) as also seen with Roc and E, leading to m/z 489.3321 (Figure A).…”

Section: Resultsmentioning

confidence: 99%

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Structural characterization of a degradation product of rocuronium using nanoelectrospray‐high resolution mass spectrometry

Wegener¹,

Harms²,

Volmer

et al. 2015

Drug Testing and Analysis

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Rocuronium bromide is a non-depolarizing neuromuscular blocking agent that causes rapid muscle relaxation after intravenous injection. Regulatory authorities for registration of pharmaceuticals for human use require the evaluation of the stability of active compounds under various stress conditions. Forced degradation of rocuronium bromide was performed under hydrolytic, thermal, photolytic, and oxidative settings. HPLC-UV/vis analysis revealed an unknown degradation product under oxidative conditions (1% H2 O2 , reflux for 1 h). Investigation of the respective HPLC fraction by high resolution mass spectrometry indicated a formal loss of CH2 and an addition of one oxygen atom to the intact drug molecule. Additional multistage mass spectrometric structural elucidation experiments aided by complementary information from analysis of the intact drug and known rocuronium-related compounds showed that the morpholine moiety was unstable under oxidative stress. The data demonstrated that the morpholine ring was opened and transformed to an N-ethanoyl-formamide group. The structure was supported by appropriate mechanistic explanations.

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Section: Resultssupporting

confidence: 65%

Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Structural characterization of a degradation product of rocuronium using nanoelectrospray‐high resolution mass spectrometry

Wegener¹,

Harms²,

Volmer

et al. 2015

Drug Testing and Analysis

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“…ROC was analyzed in human plasma by LC-MS/MS according to the method developed and validated by this research group [17]. ROC and verapamil, used as internal standard, were resolved in a reverse phase LiChrospher® 100 RP-18e Sorbent (125 × 4 mm, 5 μm; Merck, Darmstadt, Germany) a Samples of 120 μL of the mixture plasma: 1 M monobasic sodium phosphate buffer 5:1 v/v (corresponding to 100 μL plasma) were added to 1 M phosphate buffer (50 μL), 25 μL of internal standard solution (verapamil 1 μg/mL), 100 μL of a saturated solution of potassium iodide, and 2 mL of dichloromethane.…”

Section: Analysis Of Roc In Plasma By Lc-ms/msmentioning

confidence: 99%

The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries

Costa

Coelho

Lanchote

et al. 2017

Eur J Clin Pharmacol

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Purpose Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC). Methods Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A,-1032G>A,-715T>C,-361G>A, and-189_-188insA). Rocuronium pharmacokinetic parameters were estimated by non-compartmental analysis. Results None of the patients had heterozygous or homozygous variant of 404A>T, 382A>T, 502C>T, 833delA, 830C>A, 41A>G, and-715T>C. A linkage disequilibrium was found between-1105G>A and-1032G>A genotypes. Patients genotyped as-A or AA (n = 17) for SLCO1A2-189_-188InsA showed reduced total clearance of ROC compared to patients genotyped as −/− (n = 13) (151.6 vs 207.1 mL/min, p ≤ 0.05). The pharmacokinetics parameters of ROC were not significantly different between other SLCO1A2 genotypes. Conclusion SLCO1A2-189_-188InsA polymorphism is related to the reduced clearance of rocuronium in patients submitted to elective surgeries under general anesthesia. Trial registration NCT 02399397 (ClinicalTrials.gov)

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“…The concentration of rocuronium in plasma was analysed by liquid chromatography coupled with mass spectrometry, as described previously by our research group . Rocuronium and the internal standard verapamil were resolved on reversed phase column LiChrospher ® 100 RP‐18e Sorbent (Merck, Darmstadt, Germany) with 125 × 4 mm, 5 μm particle size, maintained at 25 °C and a mobile phase consisting of mixture of water: acetonitrile (50 : 50, v/v) added with 0.1% trifluoroacetic acid, flow at 1.0 ml/min.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of rocuronium in young adult and elderly patients undergoing elective surgery

Varrique¹,

Lauretti

Matsumoto

et al. 2016

Journal of Pharmacy and Pharmacology

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Analysis of rocuronium in human plasma by liquid chromatography–tandem mass spectrometry with application in clinical pharmacokinetics

Cited by 7 publications

References 20 publications

Structural characterization of a degradation product of rocuronium using nanoelectrospray‐high resolution mass spectrometry

Structural characterization of a degradation product of rocuronium using nanoelectrospray‐high resolution mass spectrometry

The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries

Pharmacokinetics and pharmacodynamics of rocuronium in young adult and elderly patients undergoing elective surgery

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