A patient receiving imipenem develops seizures. Which pharmacological principle explains why cilastatin is co-administered with imipenem and how it relates to this adverse effect?
- A Cilastatin enhances imipenem renal excretion, reducing systemic toxicity
- B Cilastatin is a beta-lactamase inhibitor that prevents imipenem hydrolysis in plasma
- C Cilastatin blocks renal dehydropeptidase-I, preventing formation of nephrotoxic metabolite; seizures arise from the accumulated parent imipenem at high CNS levels ✓
- D Cilastatin blocks GABAergic neurons in the temporal cortex
Correct answer: C. Cilastatin blocks renal dehydropeptidase-I, preventing formation of nephrotoxic metabolite; seizures arise from the accumulated parent imipenem at high CNS levels
Explanation
Renal tubular dehydropeptidase-I (DHP-I) hydrolyses imipenem to a nephrotoxic metabolite; cilastatin inhibits DHP-I, preventing this metabolism and increasing urinary imipenem concentrations. Seizures are a direct adverse effect of imipenem itself (due to GABA-A receptor antagonism), particularly at high doses or in patients with renal insufficiency. Cilastatin addresses nephrotoxicity, not seizures directly. Cilastatin has no beta-lactamase inhibitor activity.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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