Aminoglycoside nephrotoxicity predominantly involves proximal tubular injury. Which mechanism best explains why once-daily (extended-interval) dosing reduces nephrotoxicity compared to thrice-daily dosing of the same total daily dose?
- A Lower peak concentrations (Cmax) with once-daily dosing reduce direct tubular cell toxicity
- B Aminoglycosides saturate the megalin receptor at the proximal tubule brush border with once-daily high Cmax, reducing cumulative tubular uptake compared to sustained lower concentrations with thrice-daily dosing ✓
- C Once-daily dosing allows hepatic metabolism of aminoglycosides to less toxic metabolites during the dosing interval
- D Urinary alkalinisation during the longer dosing interval reduces aminoglycoside ionisation and tubular reabsorption
Correct answer: B. Aminoglycosides saturate the megalin receptor at the proximal tubule brush border with once-daily high Cmax, reducing cumulative tubular uptake compared to sustained lower concentrations with thrice-daily dosing
Explanation
Aminoglycosides are taken up into proximal tubular cells via the megalin (LRP2) receptor; once-daily dosing achieves a high Cmax that transiently saturates the megalin receptor, then the 24-hour trough period allows receptor recovery and drug release from cells. With thrice-daily dosing, lower but sustained concentrations allow cumulative, non-saturable megalin-mediated uptake, leading to greater total intracellular drug accumulation and organelle toxicity. Aminoglycosides are not hepatically metabolised (option C).
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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