Evaluation of a deuterium-labeled internal standard for the measurement of sirolimus by high-throughput HPLC electrospray ionization tandem mass spectrometry.

Clin Chem

Clinical Pharmacology and Toxicology, PathWest Laboratory Medicine, Nedlands, Australia.

Published: August 2008

AI Article Synopsis

  • The study highlights the impact of matrix effects on the accuracy of HPLC-ESI-MS/MS assays, where variability in patient samples can lead to misleading results unless properly controlled.
  • The researchers compared the effectiveness of using desmethoxyrapamycin (DMR) versus deuterium-labeled sirolimus (SIR-d(3)) as internal standards while quantifying sirolimus in whole-blood samples.
  • Results showed that SIR-d(3) provided significantly lower variability and improved accuracy in measurement compared to DMR, indicating its potential for more reliable assessments in clinical settings.

Article Abstract

Background: Matrix effects in HPLC-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS)1 can cause differences in the ionization of an internal standard (IS) compared with the analyte of interest. Unless sample cleanup or chromatographic conditions eliminate or minimize ion suppression or enhancement, variability in interpatient matrices may cause erroneous results. A stable isotope-labeled IS can be used to minimize analytical interpatient variation.

Methods: We used protein precipitation and HPLC-ESI-MS/MS to quantify sirolimus (SIR) with both desmethoxyrapamycin (DMR) and deuterium-labeled sirolimus (SIR-d(3)) as the IS to analyze a range of whole-blood and extraction-matrix samples, and to estimate recovery, matrix effects, process efficiency, and interpatient variation. We also analyzed a series of blood samples from 72 patients taking SIR, including external proficiency-testing samples, with these ISs.

Results: The range of interpatient assay imprecision (CV) values for the SIR assay was consistently lower with SIR-d(3) (2.7%-5.7%) than with DMR (7.6%-9.7%). The results obtained with the 2 different ISs for the patient samples showed a linear relationship, but the results were higher with DMR as the IS than with SIR-d(3).

Conclusions: The use of SIR-d(3) as the IS in the high-throughput HPLC-ESI-MS/MS assay of SIR yielded improved results compared with the use of DMR. SIR-d(3) appears to be less affected by differences in the ionization of SIR and its IS caused by the variability of interpatient matrices. The IS-related difference in SIR estimation needs further investigation.

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http://dx.doi.org/10.1373/clinchem.2008.103952DOI Listing

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