Metabolomic Profiling Identifies New Endogenous Markers of Tubular Secretory Clearance

Abstract

BACKGROUND: The proximal tubules eliminate protein-bound toxins and drugs via secretion. Measurements or estimates of glomerular filtration rate do not necessarily reflect the physiologically distinct process of secretion. Clinical assessment of this important intrinsic kidney function requires endogenous markers that are highly specific for secretory transport. METHODS: We used metabolomics profiling to identify candidate markers of tubular secretory clearance in 50 participants from a kidney pharmacokinetics study. We measured metabolites in three sequential plasma samples and a concurrent 10-hour timed urine sample using hydrophilic interaction liquid chromatography-high resolution mass spectrometry. We quantified the association between estimated kidney clearance and normalized plasma peak height of each candidate solute to the clearance of administered furosemide, a protein-bound, avidly secreted medication. RESULTS: We identified 528 metabolites present in plasma and urine, excluding pharmaceuticals. We found 7 highly (>50%) protein bound and 49 poorly bound solutes with clearances significantly associated with furosemide clearance, and 18 solute clearances favoring an association with furosemide clearance by the 90th percentile when compared to GFR. We also found 4 highly bound and 42 poorly bound plasma levels that were significantly associated with furosemide clearance. CONCLUSIONS: We found several candidate metabolites whose kidney clearances or relative plasma levels are highly associated with furosemide clearance, an avidly secreted tracer medication of the organic anion transporters, highlighting their potential as endogenous markers of proximal tubular secretory clearance.

Predicting complex kidney drug handling using a physiologically‐based pharmacokinetic model informed by biomarker‐estimated secretory clearance and blood flow

“…Given these inherent differences, each solute likely reflects different aspects of clearance and may therefore best predict clearance of biochemically similar compounds. Specificity to secretory clearance differs between each solute, and we continue to search for more optimal and generalizable markers of secretion 28 . This study estimated secretory clearance by fitting the model to patient‐specific KA measurements, a metabolite cleared by OAT1/3; whereas tenofovir and oseltamivir carboxylate are also largely cleared by OAT1/3, more data are needed to understand how it would apply to other drugs.…”

“…Specificity to secretory clearance differs between each solute, and we continue to search for more optimal and generalizable markers of secretion. 28 This study estimated secretory clearance by fitting the model to patient‐specific KA measurements, a metabolite cleared by OAT1/3; whereas tenofovir and oseltamivir carboxylate are also largely cleared by OAT1/3, more data are needed to understand how it would apply to other drugs. Pharmacogenomic studies reveal that variation at individual transporters can significantly modify drug clearance even at the same gross level of organ function, indicating the need for more specific markers.…”

Medium Roasting and Brewing Methods Differentially Modulate Global Metabolites, Lipids, Biogenic Amines, Minerals, and Antioxidant Capacity of Hawai‘i-Grown Coffee (Coffea arabica)

“…Metabolomics, lipidomics, and analysis of biogenic amines were conducted at the Fiehn Laboratory, NIH West Coast Metabolomics Center. Global metabolites (targeted and untargeted) were analyzed using an automated liner exchange cold injection system gas chromatography time of flight mass spectrometer (ALEX-CIS GCTOF MS) as described previously [ 87 , 88 , 89 , 90 , 91 ]. In brief, 10 mg brewed coffee samples were extracted with 1 mL of 3:3:2 acetonitrile (ACN):isopropanol (IPA):water by vortexing for 10 s and shaking for 6 min at 4 °C.…”

Estimating kidney function in patients with cancer: A narrative review

“…Drugs that are primarily excreted via proximal tubular secretion (eg, cisplatin, isofamide) are much less impacted by the patient's GFR than by their tubular function 96 . We do not currently have standardized metrics of tubular secretion that are used in clinical practice for drug dosing; however, these are under development 97 . Estimating CrCl with and without cimetidine may provide an approximation of tubular secretion until other methods are established.…”

“…96 We do not currently have standardized metrics of tubular secretion that are used in clinical practice for drug dosing; however, these are under development. 97 Estimating CrCl with and without cimetidine may provide an approximation of tubular secretion until other methods are established.…”