Cilastatin is a drug that is given with the antibiotic imipenem to delay the rapid metabolism of imipenem. Cilastatin is one of the protease inhibitors. It inhibits the renal enzyme dehydropeptidase-I, which is responsible for metabolizing imipenem.
What is cilastatin?
Cilastatin (chemical molecular formula: C16H26N2O5S) is a white to pale yellow amorphous powder (cilastatin sodium). In pharmaceuticals, it is used as a protease inhibitor, i.e., it inhibits peptidases (formerly called proteases) and thus prevents the degradation of proteins. Cilastatin inhibits the enzyme dehydropeptidase-I. The inhibition is competitive and reversible, meaning that cilastatin competes with dehydropeptidase-I to occupy the same receptors. After cilastatin is discontinued, the inhibition is reversed because the enzyme can again occupy the receptors.
Pharmacologic action
Cilastatin is used as a powder to prepare an infusion solution. From this it can be deduced that the application is always intravenous. Regarding pharmacokinetics, the plasma half-life of the drug averages one hour. Cilastatin is administered in the form of its salt cilastatin sodium. The mechanism of action of cilastatin is inhibition of dehydropeptidase-I, a renal enzyme responsible for metabolizing imipenem. There is, with concomitant administration, competitive inhibition, meaning that the cilastatin occupies the same receptors as the renal enzyme and ‘fights’ with it to occupy the receptors. Dehydropeptidase-I is thus inhibited in its activity or prevented from being active. This is the desired effect of the drug, as metabolization of imipenem is delayed by this process. Delayed metabolization results in higher concentrations and a longer duration of action of imipenem. Imipenem is hydrolyzed in the kidney, which means that it is broken down by the addition of a water molecule. This metabolization of imipenem, which is delayed by cilastatin, produces inactive nephrotoxic metabolites. In animal studies, cilastatin was shown to reduce nephrotoxicity.
Medical application and use
Cilastatin is used in fixed combination together with imipenem, an antibiotic from the ß-lactam antibiotila group. Its role is to prevent rapid metabolism of imipenem. This is necessary to obtain a sufficiently high concentration of the antibiotic for the desired therapeutic effect. Furthermore, animal studies showed a reduction in the nephrotoxic effect of imipenem when it was used in combination with cilastatin. Cilastatin itself does not have an antibacterial effect. It does not affect the antibacterial effect of imipenem; it merely prevents rapid metabolism of imipenem, which increases its concentration in plasma. Chemically, cilastatin represents a derivative of the natural amino acid (R)-cysteine. Imipenem, the antibiotic administered together with cilastatin, has a bactericidal effect via inhibition of cell wall synthesis of bacteria. There is stability against bacterial beta-lactamases. Imipenem is a broad-spectrum antibiotic that covers aerobic and anaerobic, Gram-positive and Gram-negative bacteria. It is used as a reserve antibiotic for the treatment of life-threatening bacterial infections. Mixed infections are also among the indications for imipenem. The above indications result in a strict indication for the use of the combination imipenem/cilastatin. Imipenem is always administered in combination with cilastatin for this reason.
Risks and Side Effects
Side effects and risks that may be caused by cilastatin include hypersensitivity with local tissue induration and pain; allergic reactions such as local skin irritation, redness, rash, itching, urticaria (hives); blood count changes such as thrombocytosis or eosinophilia; and transient liver dysfunction. Contraindications to cilastatin or the combination of cilastatin with imipenem include hypersensitivity to cilastatin, hypersensitivity to imipenem or other beta-lactamase antibiotics, and renal dysfunction in children. In addition, the drug should not be used during pregnancy or breastfeeding.Use in young children is also contraindicated.
