A Metabolomic Analysis of Sensitivity and Specificity of 23 Previously Proposed Biomarkers for Renal Transporter‐Mediated Drug‐Drug Interactions

Abstract

Endogenous biomarkers are discussed as tools for detection of drug‐drug interactions mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2‐K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intrastudy comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of ten previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with four inhibitors of transport proteins [verapamil (P‐glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N‐oxide were both sensitive and specific (median log2‐fold changes ‐1.18 in estimated renal elimination and ‐0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2‐fold changes ‐3.77 and ‐2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE‐ and OAT‐mediated drug‐drug interactions.

Gut-specific H3R signaling orchestrates microglia-dependent resolution of peripheral inflammation

“…Both columns were equipped with a 2.1 x 5 mm guard column, respectively (all columns from Waters, Eschborn, Germany). The applied mass spectrometric settings, LC gradients, run times, QC limits, and batch sequences were identical to those previously shown by Gessner et al (106).…”

“…LC-Orbitrap-MS-Analysis LC-MS analysis was performed as previously described (106). In brief, high-resolution mass spectrometry was done on an Exactive Focus Hybrid Quadrupole-Orbitrap mass spectrometer coupled to a Dionex Ultimate 3000 chromatographic system (both from Thermo Fisher Scientific, Dreieich, Germany).…”

Utilising Endogenous Biomarkers in Drug Development to Streamline the Assessment of Drug–Drug Interactions Mediated by Renal Transporters: A Pharmaceutical Industry Perspective

“…First, the kinetics of endogenous biomarkers can be evaluated during initial phase I trials, thereby guiding further clinical development to potentially avoid a dedicated DDI study if there is no change in the kinetics of the endogenous biomarker in the presence of the NME [ 29 ]. Factors to consider when selecting each biomarker include their selectivity, sensitivity, specificity, predictivity, robustness and ease of accessibility [ 22 , 30 – 32 ]. Second, the change in the kinetics of each endogenous biomarker should ideally reflect the interaction of the inhibitor with the activity of a single transporter, and the extent of change should be similar to one of the clinically used DDI probe drugs [ 22 , 32 ].…”