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Aristolochic acid (AA) ingestion causes Balkan nephropathy, characterized by tubular injury and progression to chronic kidney disease (CKD). AA is taken up by proximal tubule cells via organic anion transport and induces p21-mediated DNA damage response, but little is known about dietary modulating factors. Western diet (WD) is rich in saturated fats and sugars and can promote metabolic disorders and CKD progression. Here, we determined the impact of WD on AA-induced kidney injury. Five-week-old male C57BL/6J mice were fed WD or normal chow (NC) for 8 wk, followed by administration of AA every 3 days for 3 wk. Measurements were performed after the last injection and following a 3-wk recovery. Independent of dosing AA by body weight (3 mg/kg/day) or same dose/mouse (0.1125 mg/day), the AA-induced increase in plasma creatinine and reduction of hematocrit were greater in WD versus NC. This was associated with increased kidney gene expression in WD vs. NC of markers of DNA damage (p21), injury (Kim1 and Ngal), and inflammation (Tnfa) and kidney fibrosis staining. WD alone increased fractional excretion of indoxyl sulfate by 7.5-fold, indicating enhanced kidney organic anion transport. Kidney proteomics identified further WD-induced changes that could increase kidney sensitivity to AA and contribute to the altered response to AA including weakening of energy metabolism, potentiation of immune and infection pathways, and disruption in RNA regulation. In conclusion, WD can increase the susceptibility of mice to Balkan nephropathy, possibly in part through facilitating kidney uptake of the organic anion AA. NEW & NOTEWORTHY: This study shows that a Western diet (WD) aggravates a murine model of Balkan nephropathy induced by the application of the organic anion and nephrotoxin aristolochic acid (AA). Mechanistically, this may involve WD-induced kidney organic anion secretion, which can facilitate the AA uptake into proximal tubular cells and thereby contribute to the injury. Kidney proteomics identified further changes induced by feeding a WD that could have increased the sensitivity of the kidney to stress and injury. [ABSTRACT FROM AUTHOR] more...

7-Hydroxycoumarin (7-HC) is a natural coumarin compound rich in Chinese herbal medicines and has various pharmacological activities. After oral administration of 7-HC in rodents, its conjugated metabolites 7-hydroxycoumarin-β-D-glucuronide (7-HCG) and 7-hydroxycoumarin sulfate (7-HCS), exhibit high systemic exposure and urinary excretion. Organic anion transporters 1 and 3 (OAT1 and OAT3), mainly expressed in the proximal renal tubules, play an important role in drug-drug interactions and drug-induced kidney injury. We aimed to explore the mechanisms of OAT-mediated drug interactions and renal protective mechanisms of 7-HC and its conjugates. OAT-overexpressing cell models revealed that 7-HC was not a substrate for OAT1 and OAT3, while 7-HCG was specifically transported by OAT3. In contrast, 7-HCS can be transported by both OATs. Besides, 7-HC significantly inhibited the activity of OAT1 and OAT3, while 7-HCS had a strong inhibitory effect on OAT1 (IC 50 < 10 μM). After co-administration of 100 mg/kg of 7-HC to mice, systemic exposure and clearance of furosemide (a clinical substrate of OATs) were significantly increased and decreased, respectively. In addition, 7-HC decreased OAT-mediated cytotoxicity and reduced the renal distribution of adefovir in mice. Together, these findings will provide support for OAT-mediated drug interactions and the renal protection of 7-HC. [Display omitted] • 7-Hydroxycoumarin conjugates were transported by renal OAT1 and/or OAT3. • 7-Hydroxycoumarin strongly inhibited OAT1 and OAT3 in vitro with IC 50 values comparable to probenecid. • 7-Hydroxycoumarin increased systemic exposure to furosemide in mice. • 7-Hydroxycoumarin reduced OAT-mediated cytotoxicity and decreased renal concentration of adefovir in mice. [ABSTRACT FROM AUTHOR] more...

Pyridoxic acid (PDA) was suggested as a potential endogenous biomarker to assess in vivo renal organic anion transporter (OAT) 1 and 3 activity. Here, we first investigated the population variability in the plasma baseline levels of PDA using data from five independent studies (conducted/supported by Pfizer), and subsequently developed mechanistic physiologically based pharmacokinetic (PBPK) model to assess its effectiveness in biomarker-informed drug-drug interaction (DDI) predictions. Meta-analysis suggested that the inter-individual variability in PDA plasma concentration was ~40% across all five studies (n = 71 subjects). While sex-dependent differences were not evident, the baseline plasma PDA levels were significantly higher (38%, p < 0.05) in White males compared to Japanese males. Correspondingly, the amount of PDA excreted in urine and renal clearance were significantly higher (p < 0.05) in Japanese males (1.5- and 2.2-fold, respectively), compared to White males. A PBPK model considering relative activity factor-based scaling of in vitro transport data indicated > 80% contribution by OAT3 to the renal clearance of PDA. The baseline plasma concentrations across multiple studies were recovered by the model; and using in vitro inhibition potency data, the model predicted effect of OAT inhibitors (probenecid, ritlecitinib and tafamidis) on PDA pharmacokinetics. Furthermore, DDIs with OAT3 object drug, furosemide, were well-predicted by the biomarker-informed PBPK model. PDA data and the modeling approach indicated lack of clinically-relevant OAT inhibition with ritlecitinib and tafamidis. Overall, this study presents PDA as a reliable biomarker to assess OAT3-mediated renal DDIs with moderate inter-subject and inter-study variability., (© 2025 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.) more...