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Abstract ID 96950 Poster Board 233 Organic cation transporter 1 (OCT1) and OCT2 are uptake transporters of several drugs and endogenous cations, expressed on the basolateral membranes of hepatocytes and renal proximal tubule cells, respectively. Endogenous substrates of OCTs can be used as surrogate markers to predict the transporter-mediated drug-drug interaction (DDI) potential of investigational drugs.1 In this study, metabolomics analysis of plasma samples from a clinical pharmacokinetic (PK) DDI study (n=12 healthy adults) involving oral metformin (50 mg) as an OCT substrate and cimetidine (400 mg) as an OCT inhibitor was conducted to identify endogenous substrates of OCTs. Interestingly, the clinical PK study revealed that relative to baseline (metformin alone), cimetidine significantly increased (27%) metformin area under the plasma concentration-time curve (AUC0-24h) but minimally decreased renal clearance (8%), suggesting cimetidine inhibited both hepatic OCT1 and renal OCT2. To deconvolute this complex DDI, we hypothesized that variability in plasma concentrations of endogenous OCT1 or OCT2 substrates should correlate significantly with metformin plasma concentrations at baseline and in the presence of cimetidine, whereas other elevated features in plasma would be false positives. Plasma samples (pool of 1.5, 2.0, 2.5, 3.0, and 3.5 h collections) representing timepoints that captured maximum cimetidine plasma concentrations were analyzed by nanoLC-HRMS. The untargeted MS data were analyzed using XCMS online software. Approximately 6,000 individual features (m/z values) were detected in the pooled plasma samples, which were shortlisted using optimized selection criteria: (1) significant increase in the presence of cimetidine (p5-fold. Of the 73 features meeting these criteria, 14 were identified as cimetidine-related compounds, whereas 59 were identified as potential endogenous compounds affected by cimetidine. The interindividual variability in partial plasma AUCs of metformin (both in the absence and presence of cimetidine) and cimetidine were leveraged to stratify the endogenous OCT1 and OCT2 substrates. For example, six features only correlated significantly (r>0.50, pm/z 109.1, 269.2, 272.2, 287.2, and 309.1) correlated significantly with metformin concentrations at baseline and 6 features (m/z 164.1, 212.2, 272.1, 286.1, 294.2, and 302.1) correlated significantly with metformin concentrations in the presence of cimetidine (Fig.1). These 11 compounds were considered potential OCT substrates, and using metabolomics databases, were putatively identified as belonging to a diverse endogenous (e.g., opioids) or exogenous (e.g., capsinoids) origin. The renal clearances of these features and their associations with OCT1 and OCT2 genotypes from our ongoing clinical study will help elucidate the fractional contributions of hepatic OCT1 and renal OCT2 to the elimination of these substrates. Results from this study will provide an improved understanding of the physiological functions of OCT1 and OCT2 and facilitate the identification of potential biomarkers of these transporters. Reference Miyake, T. et al., (2019). Drug Metab Dispos, 47(11), 1270-1280. Funding: This work was funded by NIH/NICHD (R01HD081299) and NIH/NCCIH (U54AT008909).
Singh et al. (Mon,) studied this question.