Cilastatin is a drug used to prevent the renal metabolism of certain antibiotics, particularly imipenem, thereby increasing their effectiveness and reducing kidney toxicity. It works by inhibiting the enzyme dehydropeptidase-I in the kidneys, which would otherwise degrade the antibiotic before it can act. Cilastatin is often administered in combination with imipenem to treat severe bacterial infections, including those caused by resistant pathogens. It was developed in the late 1970s and received FDA approval in the early 1980s for clinical use.
BRAND NAMES
Primaxin – combination of imipenem and cilastatin.
Tienam – combination of imipenem and cilastatin, used in some regions outside the US.
MECHANISM OF ACTION
Cilastatin acts by inhibiting the renal enzyme dehydropeptidase-I, which normally breaks down imipenem in the kidneys. By blocking this enzyme, it prevents the degradation of imipenem, allowing higher active drug levels in the body. This enhances the antibiotic’s effectiveness and reduces the formation of toxic metabolites, thereby protecting the kidneys. Cilastatin itself has no direct antibacterial activity.
PHARMACOKINETICS
Absorption
Cilastatin is administered intravenously and is therefore completely bioavailable, bypassing the process of gastrointestinal absorption. Since it is not given orally, traditional absorption parameters do not apply. It rapidly reaches therapeutic levels in the bloodstream when administered in combination with imipenem.
Distribution
Cilastatin has a relatively low volume of distribution, typically around 0.2–0.3 L/kg, indicating that it is mainly confined to the extracellular fluid. It shows moderate plasma protein binding (about 40%) and distributes primarily in body fluids such as interstitial fluid, with limited penetration into tissues and the central nervous system.
Metabolism
Cilastatin undergoes minimal metabolism in the body. It is not significantly biotransformed and remains largely unchanged after administration. Instead of being metabolized, it primarily acts locally in the kidneys to inhibit dehydropeptidase-I and is then excreted unchanged.
Excretion
Cilastatin is primarily excreted unchanged by the kidneys through glomerular filtration and tubular secretion. A large proportion of the administered dose is eliminated in the urine within 24 hours. Its elimination is closely linked to renal function, so dose adjustments may be required in patients with impaired kidney function.
PHARMACODYNAMICS
Cilastatin is a specific inhibitor of the renal enzyme dehydropeptidase-I, and its pharmacodynamic effect is to protect imipenem from enzymatic degradation in the kidneys. By blocking this enzyme, it increases the concentration and duration of active imipenem in the body while reducing the formation of nephrotoxic metabolites. Cilastatin itself has no intrinsic antibacterial activity, but it enhances the efficacy and safety of imipenem therapy.
ADMINISTRATION
Cilastatin is given by intravenous infusion, usually with Imipenem, to prevent its breakdown in the kidneys and improve its effectiveness.
DOSAGE AND STRENGTH
Cilastatin is always administered in combination with imipenem as an intravenous infusion. The dosage is expressed based on the imipenem–cilastatin combination. In adults, the usual dose ranges from 250 mg to 1 g every 6–8 hours, depending on the severity and type of infection.
DRUG INTERACTIONS
Valproic acid: Concomitant use can significantly reduce valproic acid levels, increasing the risk of seizures.
Ganciclovir: May increase the risk of central nervous system toxicity, including seizures.
Probenecid: Can decrease renal excretion of cilastatin and imipenem, leading to increased plasma levels.
FOOD INTERACTIONS
Cilastatin is administered intravenously and is not absorbed from the gastrointestinal tract, so food does not affect its activity or bioavailability. There are no known dietary restrictions or interactions with meals.
CONTRAINDICATIONS
Cilastatin (in combination with imipenem) is contraindicated in patients with a known hypersensitivity to cilastatin, imipenem, or other β-lactam antibiotics (such as penicillins or cephalosporins). It should also be avoided in individuals with a history of severe allergic reactions (e.g., anaphylaxis) to these drugs.
SIDE EFFECTS
Cilastatin itself is generally well tolerated, but when given with imipenem, some common and less common adverse effects may occur:
Nausea and vomiting
Diarrhea
Rash
Injection site reactions
OVER DOSE
Nausea, vomiting, and diarrhea
Seizures or other central nervous system symptoms
Confusion or dizziness
TOXICITY
Cilastatin itself has low toxicity. Most adverse effects are related to imipenem and may include seizures, allergic reactions, or blood count changes, especially in patients with renal impairment.
