[Nephrotoxicity and drug interaction of vancomycin]

Area of Science:

• Pharmacology
• Nephrology
• Drug Interactions

Background:

• Vancomycin hydrochloride (VCM) is effective against Gram-positive bacteria but requires co-administration with Gram-negative agents for composite infections.
• Both VCM and imipenem (IPM) exhibit nephrotoxicity, a known adverse reaction.
• Cilastatin sodium (CS) is known to mitigate the nephrotoxicity associated with IPM.

Purpose of the Study:

• To investigate the drug interactions of VCM in rabbit kidneys.
• To evaluate the nephrotoxicity and pharmacokinetics of VCM when co-administered with CS or IPM-CS.
• To elucidate the mechanisms underlying VCM-CS interactions and VCM nephrotoxicity.

Main Methods:

• Administration of VCM (300 mg/kg, IV) to rabbits, with comparative groups receiving VCM plus CS or VCM plus IPM-CS.
• Assessment of nephrotoxicity through serum creatinine and BUN levels, and kidney morphology.
• Pharmacokinetic analysis including VCM clearance and urinary excretion.
• In vitro study of VCM uptake in rabbit renal slices to determine active transport and the effect of CS.

Main Results:

• VCM administration at 300 mg/kg induced nephrotoxicity, evidenced by elevated creatinine, BUN, and kidney morphological changes.
• Co-administration of VCM with CS or IPM-CS prevented VCM-induced nephrotoxicity and associated clinical/morphological abnormalities.
• Clearance and urinary excretion of VCM were significantly increased in rabbits treated with VCM plus CS or IPM-CS.
• VCM uptake in renal cortex slices was actively transported and significantly reduced by CS.

Conclusions:

• CS mitigates VCM nephrotoxicity, likely by inhibiting VCM uptake into renal cells.
• The co-administration of CS or IPM-CS with VCM enhances VCM clearance and urinary excretion.
• These findings suggest a novel mechanism for reducing VCM-related kidney injury in clinical settings.