Imipenem – why can’t we use it alone?

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Imipenem is a beta-lactam antibiotic that has a wide spectrum of activity against gram negative and gram positive organisms and is commonly used in an ICU setting. It is always given in combination with Cilastatin and in most of the documentation that you find online about this drug, it says that they are co-administered to increase the plasma levels of imipenem. This is not exactly true and this is where the story gets interesting from a renal point of view.
When given alone, imipenem is filtered in the glomerulus and when it reaches the proximal tubule, it is metabolized by a brush-border enzyme called dehydropeptidase I. As a result, under normal circumstances, only 5-20% of it is excreted unchanged in the urine. The metabolites of imipenem are very toxic to the proximal tubular cells and cause tubular necrosis and as a result, the drug on its own would not be useful due to its toxicity. Cilastatin inhibits the action of dehydropeptidase I, allowing the drug to be excreted unchanged in the urine and when they are given together, more than 70% of the drug reaches the urine. Some of the unmetabolized drug is reabsorbed but the peak levels increase by less than 20% and there is no alteration in the half-life. Thus, the major role of cilastatin is to prevent nephrotoxicity and increase the urinary concentration of imipenem.
So this begs the question of how it was determined that this was how the drug was metabolized. In early animal trials, the investigators noted that, despite the fact that it should be readily filtered at the glomerulus, the urine levels of imipenem were consistently far lower than would be expected given the serum levels. This could indicate that the drug was being metabolized elsewhere than the kidney but the rate of metabolism of the drug decreased significantly when the renal arteries were ligated. Finally, using porcine kidneys, the investigators determined that the enzyme responsible was dehydropeptidase I and developed cilastatin as an inhibitor of the enzyme to be co-administered with the drug.
This is the original paper concerning the pharmacokinetics of imipenem. An interesting historical renal perspective on a commonly used drug.

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