Aminoglycoside nephrotoxicity follows a specific time-course despite once-daily dosing. Which statement about its mechanism and prevention is CORRECT?

• A Aminoglycosides cause nephrotoxicity via reactive oxygen species generated by aminoglycoside-iron complexes in proximal tubular cells; once-daily dosing reduces toxicity by allowing tubular cell recovery during the trough period
• B Aminoglycosides are directly nephrotoxic by blocking podocyte TRPC5 channels in glomeruli
• C Nephrotoxicity is primarily due to renal cortex accumulation via megalin (LRP2)-mediated endocytosis in proximal tubules; once-daily dosing saturates this uptake pathway, reducing total 24-hour cortical accumulation compared to divided doses
• D Both A and C are correct mechanisms contributing to aminoglycoside nephrotoxicity ✓

Explanation

Aminoglycoside nephrotoxicity has two interrelated mechanisms: (1) Proximal tubular uptake via megalin-mediated endocytosis is saturable; extended-interval (once-daily) dosing produces a high Cmax that saturates renal cortical uptake mechanisms during the dosing period, limiting total cortical accumulation over 24 hours despite higher peak concentrations; (2) Intracellularly, aminoglycosides bind to mitochondrial membranes and ribosomes, generate reactive oxygen species through Fe2+-aminoglycoside Fenton chemistry, and damage proximal tubular cells. The low trough period also allows mitochondrial repair. These same mechanisms explain ototoxicity (stria vascularis Fe-ROS). Risk factors: age, volume depletion, concurrent nephrotoxins, pre-existing CKD.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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