Analytical and Bioanalytical Chemistry

, Volume 409, Issue 14, pp 3551–3560 | Cite as

Bioanalysis of farnesyl pyrophosphate in human plasma by high-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry and hybrid quadrupole Orbitrap high-resolution mass spectrometry

Research Paper

Abstract

The isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are pivotal intermediates for cholesterol homeostasis and cell signaling in the mevalonate pathway. We developed a sensitive and selective high-performance liquid chromatography tandem triple quadrupole mass spectrometry (LC-QQQ-MS) method for FPP in human plasma without the need for a derivatization process. We optimized the sample preparation procedure to extract FPP and 13C5-FPP (as internal standard) from sample fluids using methanol. Phosphate-buffered saline was used as the surrogate matrix for the preparation of calibration curves and quality control samples. Using an XBridge C18 column (3.5 μm, 2.1 × 100-mm ID) with gradient elution composed of 10 mmol/L ammonium carbonate/ammonium hydroxide (1000:5, v/v) and acetonitrile/ammonium hydroxide (1000:5, v/v) provided the sharp peaks of FPP and 13C5-FPP in human plasma. The calibration curve ranged from 0.2 to 20 ng/mL in human plasma with acceptable intra-day and inter-day precision and accuracy. The sensitivity of this bioanalytical method was sufficient for clinical analysis. The endogenous FPP plasma concentrations in 40 human healthy volunteers ascertained by LC-QQQ-MS and high-performance liquid chromatography tandem hybrid quadrupole Orbitrap high-resolution mass spectrometry (LC-Q-Orbi-MS) were comparable. Furthermore, the endogenous GGPP in human plasma was selectively detected for the first time by LC-Q-Orbi-MS. In conclusion, a sensitive bioanalytical method for FPP in human plasma by means of LC-QQQ-MS and LC-Q-Orbi-MS was developed in this study. Taking into account the versatility of LC-Q-Orbi-MS, the simultaneous detection of FPP and GGPP may be feasible in clinical practice.

Keywords

Farnesyl pyrophosphate Geranylgeranyl pyrophosphate Surrogate matrix LC-QQQ-MS LC-Q-Orbi-MS 

Notes

Acknowledgements

We are thankful to Mr. Koichi Iida at Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, for fruitful discussion about the application of high-resolution mass spectrometry for the quantification of mevalonate-derived isoprenoid intermediates. We appreciate Mr. Shio Watanabe at the Application Group, LC-MS Chromatography & MS Department, Thermo Fisher Scientific, Japan, for his excellent analytical support with LC-Q-Orbi-MS.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research DivisionTakeda Pharmaceutical Company LimitedFujisawaJapan

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