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.
Six BAs are quantified in human plasma using a multiplexed high-resolution mass spectrometry method. Glycodeoxycholic acid 3-sulfate and glycodeoxycholic acid 3-O-β-glucuronide are proposed as potential biomarkers based on observed four- to fivefold increase in plasma AUC (vs placebo), following administration of a compound known to present as an OATP1B1/3 inhibitor in vitro.
1-NMN plasma AUCs increased two- to fourfold versus placebo following the administration of a clinical candidate that in vitro experiments indicated was an OCT2 inhibitor. The described hydrophilic interaction liquid chromatography-MS/MS assay can be used to assess a clinical compound candidate for the inhibition of OCT2 and multidrug and toxin extrusion protein transporter in first-in-human studies.
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