High-Altitude Hypoxia Dysregulates the Organic Anion Transport Network to Alter Acetazolamide Disposition and Renal Metabolic Homeostasis: Validation of the Remote Sensing and Signaling Theory.

Acute high-altitude hypoxia (AHH) disrupts systemic homeostasis and alters the pharmacokinetic (PK) profiles of drugs, yet the role of the organic anion transport network in mediating altered drug disposition and the link to regulation by the Remote Sensing and Signaling Theory remain unclear. Moreover, the underlying mechanisms governing the PK of acetazolamide (ACZ), an FDA-approved therapeutic agent for high-altitude illness, remain unelucidated. This study aimed to clarify the effects of AHH on the PK of ACZ, identify the organic anion transport network involved, and characterize perturbations in renal metabolism. Results demonstrated that AHH markedly altered ACZ PK: with a 3.27-fold increase in AUC0-∞ and a 2.62-fold prolongation in t1/2. For the first time, ACZ was confirmed as a specific substrate of organic anion transporter 1, multidrug resistance-related protein (MRP4), and breast cancer resistance protein. Mechanistically, AHH dysregulated these transporters, including upregulating breast cancer resistance protein, downregulating organic anion transporters, organic anion transporting polypeptides, MRPs, and P-glycoprotein via transcriptional regulation of nuclear receptors (hypoxia-inducible factor-1α, Pregnane X receptor, constitutive androstane receptor, and hepatocyte nuclear factor-4α), a finding validated in acute hypoxic Caco-2 cells and AHH rat models. Renal metabolomics further revealed profound perturbations in organic anion metabolism, notably, indoxyl sulfate, hippuric acid, and kynurenic acid were decreased by 56.84%, 88.53%, and 69.77%, respectively, whereas estrone glucuronide was elevated 4.78-fold, and these 4 metabolites were identified as novel renal tissue-specific biomarkers of AHH-induced renal organic anion transport network dysfunction. Collectively, this study elucidates organic anionic drug disposition mechanisms under AHH, validates Remote Sensing and Signaling Theory by linking organic anion transport network to drug metabolism crosstalk, and provides evidence for personalized pharmacotherapy of high-altitude sickness. SIGNIFICANCE STATEMENT: This study uncovers how acute high-altitude hypoxia dysregulates the organic anion transport network to disrupt acetazolamide (ACZ) disposition and renal metabolic homeostasis. It first identifies ACZ as an organic anion transporter 1/multidrug resistance-related protein 4/breast cancer resistance protein substrate and defines indoxyl sulfate, hippuric acid, kynurenic acid, and estrone glucuronide as endogenous renal tissue-specific biomarkers for organic anion transport network dysfunction. Filling the gap in understanding acute high-altitude hypoxia-mediated organic anion transport network regulation, this work validates the Remote Sensing and Signaling Theory and provides critical insights for optimizing ACZ pharmacotherapy and exploring metabolic homeostasis in high-altitude environments.