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

均龙胆酸 碱尿 色谱法 化学 超滤(肾) 质谱法 液相色谱-质谱法 串联质谱法 酪氨酸 酪氨酸血症 生物化学
作者
Andrew T. Hughes,Anna M. Milan,Andrew Davison,Peter Christensen,Gordon Ross,James A. Gallagher,John Dutton,L. Ranganath
出处
期刊:Annals of Clinical Biochemistry [SAGE]
卷期号:52 (5): 597-605 被引量:52
标识
DOI:10.1177/0004563215571969
摘要

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 = 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℃. The assay was linear to 500μmol/L homogentisic acid, 2000μmol/L tyrosine and 10μmol/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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