The molecular clock: a focus on chronopharmacological strategies for a possible control of aminoglycoside renal toxicity

Chronotherapy applies biological rhythmicity in order to optimize clinical treatments, relating the dosing time of the drugs to the daily variations of their therapeutic and unwanted side effects due to the fluctuations in physiological processes involved in their pharmacokinetics and/or pharmacodynamics. The goal of chronotherapy is to administer treatments at the time of day that enhances both their effectiveness and tolerance. This review intends to (1) provide the theoretical rationale behind the use of aminoglycosides during extended interval schedule chronotherapy in clinical practice and (2) target the underlying molecular mechanisms of renal toxicity, the main unwanted side effect. Previous reports suggest that aminoglycoside therapy may benefit from a chronopharmacological approach. Temporal variations in the renal blood flow and glomerular filtration rate and several clock-dependent molecular mechanisms contributing to the daily changes in electrolyte and water urinary excretion have been reported. Daily differences in aminoglycoside toxicity and kinetic disposition have been found in laboratory animals and human patients. Nephrotoxicity and renal cortical accumulation are higher when drugs are administered during the rest phase than during the active phase. Active translocation of aminoglycosides into renal cells is mediated by the megalin/cubilin receptor complex located at the luminal epithelial cell membrane. The complex regulation of this endocytic mechanism deserves further study, in order to dilucidate the molecular bases that may be involved in chrono- therapeutic strategies developed for minimizing aminoglycoside accumulation in the renal cells, and thus, increasing their tolerance.