A Multiplexed HILIC-MS/HRMS Assay for the Assessment of Transporter Inhibition Biomarkers in Phase I Clinical Trials: Isobutyryl-Carnitine as an Organic Cation Transporter (OCT1) Biomarker
- 18 June 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Analytical Chemistry
- Vol. 92 (14), 9745-9754
- https://doi.org/10.1021/acs.analchem.0c01144
Abstract
There is a growing interest in using endogenous compounds as drug transporter biomarkers to facilitate drug–drug interaction (DDI) risk assessment in early phase I clinical trials. Compared to other drug transporters, however, no valid biomarker for hepatic organic cation transporter (OCT) 1 has been described to date. The present work represents the first report of an endogenous compound, isobutyryl-l-carnitine (IBC), as a potential clinical OCT1 biomarker for DDI assessment. A hydrophilic interaction chromatography (HILIC)-mass spectrometry/high resolution mass spectrometry (MS/HRMS) assay with a simple sample preparation method was developed. The assay is capable of simultaneously quantifying multiple endogenous compounds, including IBC, thiamine, N1-methylnicotinamide (1-NMN), creatinine, carnitine, and metformin, which is a probe for OCT1 and OCT2 and MATE1 and MATE2K (multidrug and toxin extrusion proteins) in clinical studies. The HRMS assay was fit-for-purpose validated in human plasma and demonstrated good linearity, accuracy, and precision for all analytes. It was further applied to two phase I clinical trials to evaluate potential biomarkers for OCT1 and additional cation transporters (renal OCT2, MATE1, and MATE2K). The clinical data demonstrated that plasma IBC changes correlated well with in vitro data and supported its use as a liver OCT1 biomarker. The described HILIC-MS/HRMS assay can be used as a “biomarker cocktail” to simultaneously assess clinical DDI risk for the inhibition of OCT1/2 and MATEs in clinical studies with new drug candidates.Keywords
This publication has 39 references indexed in Scilit:
- Identification of Novel Substrates and Structure–Activity Relationship of Cellular Uptake Mediated by Human Organic Cation Transporters 1 and 2Journal of Medicinal Chemistry, 2013
- Development and Validation of an LC/MS Method for Quantitative Determination of Thiamine in Blood PlasmaPharmaceutical Chemistry Journal, 2013
- Integrated quantitative and qualitative workflow for in vivo bioanalytical support in drug discovery using hybrid Q-TOF-MSBioanalysis, 2012
- Direct injection of lipophilic compounds in the organic phase from liquid–liquid extracted plasma samples onto a reversed-phase columnBioanalysis, 2011
- Human metabolic individuality in biomedical and pharmaceutical researchNature, 2011
- Novel MS solutions inspired by MISTBioanalysis, 2010
- Membrane transporters in drug developmentNature Reviews Drug Discovery, 2010
- Liquid chromatography/mass spectrometry determination of endogenous plasma acetyl and palmitoyl carnitines as potential biomarkers ofβ-oxidation in miceRapid Communications in Mass Spectrometry, 2008
- Quantification of Carnitine and Acylcarnitines in Biological Matrices by HPLC Electrospray Ionization– Mass SpectrometryClinical Chemistry, 2008
- Drug excretion mediated by a new prototype of polyspecific transporterNature, 1994