In vivo solid phase microextraction for therapeutic monitoring and pharmacometabolomic fingerprinting of lung during in vivo lung perfusion of FOLFOX

Nikita Looby; Anna Roszkowska; Miao Yu; German Rios-Gomez; Mauricio Pipkin; Barbara Bojko; Marcelo Cypel; Janusz Pawliszyn

doi:10.1016/j.jpha.2023.04.005

In vivo solid phase microextraction for therapeutic monitoring and pharmacometabolomic fingerprinting of lung during in vivo lung perfusion of FOLFOX

J Pharm Anal. 2023 Oct;13(10):1195-1204. doi: 10.1016/j.jpha.2023.04.005. Epub 2023 Apr 12.

Authors

Nikita Looby¹, Anna Roszkowska^{1

2}, Miao Yu¹, German Rios-Gomez¹, Mauricio Pipkin³, Barbara Bojko⁴, Marcelo Cypel³, Janusz Pawliszyn¹

Affiliations

¹ Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada.
² Department of Pharmaceutical Chemistry, Medical University of Gdansk, 80-416, Gdansk, Poland.
³ Division of Thoracic Surgery, University Health Network, TGH, 200 Elizabeth St, Toronto, ON, M5G 2C4, Canada.
⁴ Department of Pharmacodynamics and Molecular Pharmacology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-089, Bydgoszcz, Poland.

Abstract

In vivo lung perfusion (IVLP) is a novel isolated lung technique developed to enable the local, in situ administration of high-dose chemotherapy to treat metastatic lung cancer. Combination therapy using folinic acid (FOL), 5-fluorouracil (F), and oxaliplatin (OX) (FOLFOX) is routinely employed to treat several types of solid tumours in various tissues. However, F is characterized by large interpatient variability with respect to plasma concentration, which necessitates close monitoring during treatments using of this compound. Since plasma drug concentrations often do not reflect tissue drug concentrations, it is essential to utilize sample-preparation methods specifically suited to monitoring drug levels in target organs. In this work, in vivo solid-phase microextraction (in vivo SPME) is proposed as an effective tool for quantitative therapeutic drug monitoring of FOLFOX in porcine lungs during pre-clinical IVLP and intravenous (IV) trials. The concomitant extraction of other endogenous and exogenous small molecules from the lung and their detection via liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) enabled an assessment of FOLFOX's impact on the metabolomic profile of the lung and revealed the metabolic pathways associated with the route of administration (IVLP vs. IV) and the therapy itself. This study also shows that the immediate instrumental analysis of metabolomic samples is ideal, as long-term storage at -80 °C results in changes in the metabolite content in the sample extracts.

Keywords: Chemotherapy; In vivo lung perfusion; Metabolomics; Solid-phase microextraction; Therapeutic drug monitoring.