Introduction: Plasma metanephrines (PMETS) are widely used as a first-line investigation for phaeochromocytoma/paraganglioma owing to the high diagnostic sensitivity of the test. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become the methodology of choice for measuring PMETS due to the high analytical specificity of the technique. However, there have been recent reports of interference in LC-MS/MS PMETS assays by the α1-receptor agonist midodrine.
Methods: Potential interference of both midodrine (prodrug) and desglymidodrine (active metabolite) in our PMETS LC-MS/MS assay was investigated by spiking known concentrations of these compounds into pooled patient serum. Midodrine and desglymidodrine were added at concentrations of 0, 5, 10, 15, 20 and 25 nmol/L. Plasma normetanephrine, metanephrine and 3-methoxytyramine were measured in blank and spiked serum (5 replicate analyses).
Results: In the case of midodrine, no interference was observed for normetanephrine or 3-methoxytyramine, but there was a dose-related increase in measured metanephrine. The increase in the metanephrine signal was equivalent to around 18% of the midodrine concentration. In the case of desglymidodrine there was no interference in normetanephrine but evidence of interference in metanephrine and 3-methoxytyramine. This was equivalent to around 5% for metanephrine and 1% for 3-methoxytyramine. On examination of the chromatograms there was an obvious peak eluting immediately before metanephrine in samples spiked with desglymidodrine.
Conclusions: Midodrine and desglymidodrine cause interference in our LC-MS/MS method for PMETS, particularly for metanephrine. Although this interference should be detected through routine visual inspection of chromatograms (and results not reported where interference is suspected), this is likely dependent on desglymidodrine concentration and there is a possibility that this could go undetected in the laboratory. Users should therefore be aware that PMETS LC-MS/MS assays may suffer from interference where patients are taking midodrine. We are investigating changes to the chromatography in our assay, aiming to overcome midodrine interference.