Liquid chromatography tandem mass spectrometry method for the quantitation of NTBC (2-(nitro-4-trifluoromethylbenzoyl)1,3-cyclohexanedione) in plasma of tyrosinemia type 1 patients

Herebian, Diran; Spiekerkötter, Ute; Lamshöft, Marc; Thimm, Eva; Laryea, Maurice D.; Mayatepek, Ertan

doi:10.1016/j.jchromb.2009.03.014

Cited by 26 publications

(30 citation statements)

References 7 publications

(6 reference statements)

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“…5 For this method the same isocratic elution mode was used consisting of 60% acetonitrile and 40% water (0.1% formic acid, 0.01% TFA).…”

Section: Resultsmentioning

confidence: 99%

“…4 Recently, we have demonstrated a sensitive and selective liquid chromatography/tandem mass spectrometry (LC/ MS/MS) method for the determination of the NTBC content in plasma of HT-1 patients for optimal individual dose adaptation, drug response and pharmaco-/toxicokinetic studies. 5 An interpatient variability in drug metabolism could clearly be observed confirming the necessity of drug monitoring application during therapy. NTBC is registered as an orphan drug and knowledge of its metabolites present in urine is important to provide a better understanding of its metabolic fate.…”

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confidence: 87%

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Identification of NTBC metabolites in urine from patients with hereditary tyrosinemia type 1 using two different mass spectrometric platforms: triple stage quadrupole and LTQ-Orbitrap

Herebian

Lamshöft

Mayatepek

et al. 2010

Rapid Commun. Mass Spectrom.

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The objective of our work was to identify known and unknown metabolites of the drug NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione) in urine from patients during the treatment of hereditary tyrosinemia type 1 (HT-1) disease, a severe inborn error of tyrosine metabolism. Two different mass spectrometric techniques, a triple stage quadrupole and an LTQ-Orbitrap (Fourier transform mass spectrometry (FTMS)), were used for the identification and the structural elucidation of the detected metabolites. Initially, the mass spectrometric (MS) approach consisted of the precursor ion scan detection of the selected product ions, followed by the corresponding collision-induced dissociation (CID) fragmentation analysis (MS(2)) for the targeted selected reaction monitoring (SRM) mode. Subsequently, accurate and high-resolution full scan and MS/MS measurements were performed on the possible metabolites using the LTQ-Orbitrap. Final confirmation of the identified metabolites was achieved by measuring commercially supplied or laboratory-synthesized standards. Altogether six metabolites, including NTBC itself, were extracted, detected and identified. In addition, two new NTBC metabolites were unambiguously identified as amino acid conjugates, namely glycine-NTBC and beta-alanine-NTBC. These identifications were based on their characteristics of chromatographic retention times, protonated molecular ions, elemental compositions, product ions (using CID and higher-energy C-trap dissociation (HCD) techniques) and synthesized references. The applied MS strategy, based on two different MS platforms (LC/MS/MS and FTMS), allowed the rapid identification analysis of the drug metabolites from human extracts and could be used for pharmaceutical research and drug development.

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“…5 For this method the same isocratic elution mode was used consisting of 60% acetonitrile and 40% water (0.1% formic acid, 0.01% TFA).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 87%

Identification of NTBC metabolites in urine from patients with hereditary tyrosinemia type 1 using two different mass spectrometric platforms: triple stage quadrupole and LTQ-Orbitrap

Herebian

Lamshöft

Mayatepek

et al. 2010

Rapid Commun. Mass Spectrom.

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“…[17][18][19] Combined methods suitable for monitoring HT-1 have measured NTBC with several amino acids and metabolites in blood spots, suitable for paediatrics. 20,21 To date there has been no published method for simultaneously monitoring NTBC, HGA and tyrosine concentrations in serum.…”

Section: Introductionmentioning

confidence: 99%

Serum markers in alkaptonuria: simultaneous analysis of homogentisic acid, tyrosine and nitisinone by liquid chromatography tandem mass spectrometry

et al. 2015

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Background: Alkaptonuria is a rare debilitating autosomal recessive disorder of tyrosine metabolism, where deficiency of homogentisate 1,2-dioxygenase results in increased homogentisic acid. Homogentisic acid is deposited as an ochronotic pigment in connective tissues, especially cartilage, leading to a severe early onset form of osteoarthritis, increased renal and prostatic stone formation and hardening of heart vessels. Treatment with the orphan drug, nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase has been shown to reduce urinary excretion of homogentisic acid. Method: A reverse phase liquid chromatography tandem mass spectrometry method has been developed to simultaneously analyse serum homogentisic acid, tyrosine and nitisinone. Using matrix-matched calibration standards, two product ion transitions were identified for each compound (homogentisic acid, tyrosine, nitisinone) and their respective isotopically labelled internal standards ( 13 C 6 -homogentisic acid, d 2 -tyrosine, 13 C 6 -nitisinone). Results: Intrabatch accuracy was 94-108% for homogentisic acid, 95-109% for tyrosine and 89-106% for nitisinone; interbatch accuracy (n ¼ 20) was 88-108% for homogentisic acid, 91-104% for tyrosine and 88-103% for nitisinone. Precision, both intra-and interbatch were <12% for homogentisic acid and tyrosine, and <10% for nitisinone. Matrix effects observed with acidified serum were normalized by the internal standard (<10% coefficient of variation). Homogentisic acid, tyrosine and nitisinone proved stable after 24 h at room temp, three freeze-thaw cycles and 24 h at 4 C. The assay was linear to 500mol/L homogentisic acid, 2000mol/L tyrosine and 10mol/L nitisinone; increased range was not required for clinical samples and no carryover was observed. Conclusions:The method developed and validated shows good precision, accuracy and linearity appropriate for the monitoring of alkaptonuria patients, pre-and post-nitisinone therapy.

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“…A column liquid chromatographic method, a liquid chromatographic-tandem mass spectrometry (LC-MS/MS); a capillary electrophoretic method with photometric detection and a high-performance liquid chromatographic-tandem mass spectrometric method have been applied for the detection and quantitative determination of nitisinone in serum, plasma and dried blood spot samples. [49][50][51][52][53][54] Although the mean plasma nitisinone concentration which is theoretically sufficient to produce a 99.9% inhibition of HPPD based on in vitro studies has been determined to be 35 µmol/L, it is quite common that some HT1 patients require higher plasma levels (<70 µmol/L) to achieve complete elimination of urinary SA excretion. 8,11 As plasma SA is protein bound, plasma SA level and δ-aminolevulinic acid (ALA) dehydratase inhibition take longer to normalize.…”

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confidence: 99%

“…Schlune et al proposed plasma nitisinone levels of 45-50 µmol/L, Herebian et al proposed plasma nitisinone levels of 50-150 µmol/L and Prieto et al proposed plasma nitisinone levels of 15-40 µmol/L. 16,49,50 Administration of nitisinone in two divided daily doses is recommended but administration of a single daily dose which is found to be well tolerated and safe, potentially improving compliance with therapy, also results in therapeutic plasma drug levels and effective suppression of SA formation. 8,16,45 effects of nitisinone on the hepatic manifestations of HT1…”

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confidence: 99%

Nitisinone: a review

Aktuglu-Zeybek¹,

Zübarioğlu²

2017

ODRR

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Nitisinone (2-[2-nitro-4-trifluoromethylbenzoyl]cyclohexane-1,3-dione), an effective triketone herbicide, is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, the second enzyme in the tyrosine catabolic pathway. Since 1992, the drug has become an effective pharmacological treatment for hereditary tyrosinemia type 1 (HT1). Nitisinone can prevent the development of liver disease, reverse and prevent the renal tubular dysfunction, severe neurological crisis and cardiomyopathy and significantly reduce the risk of developing hepatocellular carcinoma in HT1 patients. Its mode of action, with few side effects reported, make the drug a potential candidate for the treatment of other disorders of tyrosine metabolism, including alkaptonuria, with successful reduction in homogentisic acid production to prevent long-term complications. Nitisinone could also be a promising agent in the treatment of tumors with active tyrosine metabolic pathways. In this review, we discuss the effects of nitisinone for various tyrosine pathway disorders.

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Liquid chromatography tandem mass spectrometry method for the quantitation of NTBC (2-(nitro-4-trifluoromethylbenzoyl)1,3-cyclohexanedione) in plasma of tyrosinemia type 1 patients

Cited by 26 publications

References 7 publications

Identification of NTBC metabolites in urine from patients with hereditary tyrosinemia type 1 using two different mass spectrometric platforms: triple stage quadrupole and LTQ-Orbitrap

Identification of NTBC metabolites in urine from patients with hereditary tyrosinemia type 1 using two different mass spectrometric platforms: triple stage quadrupole and LTQ-Orbitrap

Serum markers in alkaptonuria: simultaneous analysis of homogentisic acid, tyrosine and nitisinone by liquid chromatography tandem mass spectrometry

Nitisinone: a review

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