Cilastatin
Identification
- Name
- Cilastatin
- Accession Number
- DB01597
- Description
Cilastatin is an inhibitor of renal dehydropeptidase, an enzyme responsible for both the metabolism of thienamycin beta-lactam antibiotics as well as conversion of leukotriene D4 to leukotriene E4. Since the antibiotic, imipenem, is one such antibiotic that is hydrolyzed by dehydropeptidase, cilastatin is used in combination with imipenem to prevent its metabolism. The first combination product containing both drugs was approved by the FDA in November of 1985 under the trade name Primaxin, marketed by Merck & Co.9 A newer triple-drug product was approved in July 2019 under the trade name Recarbrio which also contains relebactam.8
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Cilastatin (DB01597)
- Weight
- Average: 358.453
Monoisotopic: 358.156242642 - Chemical Formula
- C16H26N2O5S
- Synonyms
- (L)-7-(2-Amino-2-carboxy-ethylsulfanyl)-2-[(2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acid
- (Z)-(S)-6-carboxy-6-[(S)-2,2-dimethylcyclopropanecarboxamido]hex-5-enyl-L-cysteine
- (Z)-7-((R)-2-Amino-2-carboxy-ethylsulfanyl)-2-[((S)-2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acid
- Cilastatin
- Cilastatina
- Cilastatine
- Cilastatinum
Pharmacology
- Indication
Cilastatin is indicated, in combination with imipenem with or without relebactam, for the treatment of bacterial infections including respiratory, skin, bone, gynecologic, urinary tract, and intra-abdominal as well as septicemia and endocarditis.6,5
- Associated Conditions
- Bloodstream Infections
- Bone and Joint Infections
- Complicated Intra-Abdominal Infections
- Complicated Urinary Tract Infection
- Endocarditis caused by staphylococcus aureus
- Gynaecological infection
- Intra-Abdominal Infections
- Lower respiratory tract infection bacterial
- Neutropenic Fever
- Pyelonephritis
- Skin and Subcutaneous Tissue Bacterial Infections
- Surgical Site Infections
- Uncomplicated Urinary Tract Infections
- Hepatic abscess
- Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
Learn More- Pharmacodynamics
Cilastatin is a chemical compound which inhibits the human enzyme dehydropeptidase.6,5 Renal Dehydropeptidase degrades the antibiotic imipenem. Cilastatin is therefore combined intravenously with imipenem in order to protect it from dehydropeptidase and prolong its antibacterial effect. However, cilastatin in and of itself does not have any antibacterial activity. The increased renal excretion of unchanged imipenem appears to prevent proximal tubular necrosis associated with high doses of imipenem.2
- Mechanism of action
Cilastatin is a renal dehydropeptidase-I inhibitor.6,5 Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to block the metabolism of imipenem.
Target Actions Organism ADipeptidase 1 inhibitorHumans - Absorption
- Not Available
- Volume of distribution
Cilastatin has a volume of distribution of 14.6-20.1L.3
- Protein binding
Cilastatin is plasma protein binding is reported to be 35-40%.5,6,3
- Metabolism
- Not Available
- Route of elimination
Cilastatin is reported by official FDA labeling to be 70% excreted in the urine, however published literature has reported values as high as 98%.3
- Half-life
- Clearance
Cilastatin has a total clearance of 0.2 L/h/kg and a renal clearance of 0.10-0.16 L/h/kg.3
- Adverse Effects
Learn about our commercial Adverse Effects data.
Learn More- Toxicity
In case of overdose with the combination product, including relebactam and imipenem, it is recommended to provide supportive care.5 Imipenem, cilastatin, and relebactam may be removed via hemodialysis.
- Affected organisms
- Humans and other mammals
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Unlock Additional DataAcyclovir The excretion of Acyclovir can be decreased when combined with Cilastatin. Adefovir dipivoxil The excretion of Adefovir dipivoxil can be decreased when combined with Cilastatin. Allopurinol The excretion of Allopurinol can be decreased when combined with Cilastatin. Alprostadil The excretion of Alprostadil can be decreased when combined with Cilastatin. Aminohippuric acid The excretion of Aminohippuric acid can be decreased when combined with Cilastatin. Avibactam The excretion of Avibactam can be decreased when combined with Cilastatin. Baricitinib The excretion of Baricitinib can be decreased when combined with Cilastatin. Benzylpenicillin The excretion of Benzylpenicillin can be decreased when combined with Cilastatin. Bumetanide The excretion of Bumetanide can be decreased when combined with Cilastatin. Captopril The excretion of Captopril can be decreased when combined with Cilastatin. Additional Data Available- Extended DescriptionExtended DescriptionAvailable for Purchase
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more - SeveritySeverityAvailable for Purchase
A severity rating for each drug interaction, from minor to major.
Learn more - Evidence LevelEvidence LevelAvailable for Purchase
A rating for the strength of the evidence supporting each drug interaction.
Learn more - ActionActionAvailable for Purchase
An effect category for each drug interaction. Know how this interaction affects the subject drug.
Learn more
- Food Interactions
- No interactions found.
Products
- Product Ingredients
Ingredient UNII CAS InChI Key Cilastatin sodium 5428WXZ74M 81129-83-1 QXPBTTUOVWMPJN-QBNHLFMHSA-M - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Imipenem and Cilastatin Cilastatin sodium (500 mg/100mL) + Imipenem monohydrate (500 mg/100mL) Injection, powder, for solution Intravenous Hospira, Inc. 2011-11-17 2016-03-31 US 
Imipenem and Cilastatin Cilastatin sodium (250 mg/100mL) + Imipenem monohydrate (250 mg/100mL) Injection, powder, for solution Intravenous Hospira, Inc. 2011-11-17 2015-05-31 US Imipenem and Cilastatin Cilastatin sodium (500 mg/20mL) + Imipenem monohydrate (500 mg/20mL) Injection, powder, for solution Intravenous Fresenius Kabi USA, LLC 2012-01-03 Not applicable US Imipenem and Cilastatin Cilastatin sodium (500 mg/1) + Imipenem monohydrate (500 mg/1) Injection, powder, for solution Intravenous Cardinal Health 2012-01-03 2014-04-30 US Imipenem and Cilastatin Cilastatin sodium (250 mg/20mL) + Imipenem monohydrate (250 mg/20mL) Injection, powder, for solution Intravenous Fresenius Kabi USA, LLC 2012-01-03 Not applicable US Imipenem and Cilastatin for Injection Cilastatin (500 mg) + Imipenem (500 mg) Powder, for solution Intravenous Pfizer Canada Ulc 2011-05-02 2019-06-28 Canada 
Imipenem and Cilastatin for Injection Cilastatin (250 mg) + Imipenem (250 mg) Powder, for solution Intravenous Pfizer Canada Ulc Not applicable Not applicable Canada Imipenem and Cilastatin for Injection USP Cilastatin (500 mg) + Imipenem (500 mg) Powder, for solution Intravenous Sandoz Canada Incorporated 2010-12-21 Not applicable Canada Imipenem and Cilastatin for Injection USP Cilastatin (250 mg) + Imipenem (250 mg) Powder, for solution Intravenous Sandoz Canada Incorporated 2010-12-21 Not applicable Canada Imipenem and Cilastatin for Injection, USP Cilastatin (250 mg) + Imipenem (250 mg) Powder, for solution Intravenous Methapharm, Inc. Not applicable Not applicable Canada
Categories
- ATC Codes
- J01DH51 — Imipenem and cilastatin
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as n-acyl-alpha amino acids. These are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- N-acyl-alpha amino acids
- Alternative Parents
- L-cysteine-S-conjugates / L-alpha-amino acids / Medium-chain fatty acids / Unsaturated fatty acids / Cyclopropanecarboxylic acids and derivatives / Dicarboxylic acids and derivatives / Amino acids / Secondary carboxylic acid amides / Sulfenyl compounds / Carboxylic acids show 6 more
- Substituents
- Aliphatic homomonocyclic compound / Alpha-amino acid / Amine / Amino acid / Carbonyl group / Carboxamide group / Carboxylic acid / Cyclopropanecarboxylic acid or derivatives / Cysteine or derivatives / Dialkylthioether show 21 more
- Molecular Framework
- Aliphatic homomonocyclic compounds
- External Descriptors
- non-proteinogenic L-alpha-amino acid, L-cysteine derivative, organic sulfide, carboxamide (CHEBI:3697)
Chemical Identifiers
- UNII
- 141A6AMN38
- CAS number
- 82009-34-5
- InChI Key
- DHSUYTOATWAVLW-WFVMDLQDSA-N
- InChI
- InChI=1S/C16H26N2O5S/c1-16(2)8-10(16)13(19)18-12(15(22)23)6-4-3-5-7-24-9-11(17)14(20)21/h6,10-11H,3-5,7-9,17H2,1-2H3,(H,18,19)(H,20,21)(H,22,23)/b12-6-/t10-,11+/m1/s1
- IUPAC Name
- (2Z)-7-{[(2R)-2-amino-2-carboxyethyl]sulfanyl}-2-{[(1S)-2,2-dimethylcyclopropyl]formamido}hept-2-enoic acid
- SMILES
- CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O
References
- Synthesis Reference
Yatendra Kumar, "Process for the preparation of amorphous cilastatin sodium." U.S. Patent US20040152780, issued August 05, 2004.
US20040152780- General References
- Keynan S, Hooper NM, Felici A, Amicosante G, Turner AJ: The renal membrane dipeptidase (dehydropeptidase I) inhibitor, cilastatin, inhibits the bacterial metallo-beta-lactamase enzyme CphA. Antimicrob Agents Chemother. 1995 Jul;39(7):1629-31. [PubMed:7492120]
- Buckley MM, Brogden RN, Barradell LB, Goa KL: Imipenem/cilastatin. A reappraisal of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1992 Sep;44(3):408-44. [PubMed:1382937]
- Balfour JA, Bryson HM, Brogden RN: Imipenem/cilastatin: an update of its antibacterial activity, pharmacokinetics and therapeutic efficacy in the treatment of serious infections. Drugs. 1996 Jan;51(1):99-136. doi: 10.2165/00003495-199651010-00008. [PubMed:8741235]
- Koller M, Brom J, Raulf M, Konig W: Cilastatin (MK 0791) is a potent and specific inhibitor of the renal leukotriene D4-dipeptidase. Biochem Biophys Res Commun. 1985 Sep 16;131(2):974-9. doi: 10.1016/0006-291x(85)91335-x. [PubMed:3863619]
- FDA: Recarbrio Label [Link]
- FDA: Primaxin Label [Link]
- ChemSpider: Cilastatin [Link]
- FDA Approved Drug Products: Apadaz (benzhydrocodone and acetaminophen) tablets [Link]
- Drugs@FDA: Primaxin [Link]
- External Links
- Human Metabolome Database
- HMDB0015535
- KEGG Drug
- D07698
- KEGG Compound
- C01675
- PubChem Compound
- 6435415
- PubChem Substance
- 46505611
- ChemSpider
- 4940183
- BindingDB
- 50367502
- 2540
- ChEBI
- 3697
- ChEMBL
- CHEMBL766
- ZINC
- ZINC000004095696
- Therapeutic Targets Database
- DAP000632
- PharmGKB
- PA448998
- PDBe Ligand
- CIL
- Wikipedia
- Cilastatin
- FDA label
- Download (616 KB)
- MSDS
- Download (45 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Prevention Acute Pancreatitis (AP) 1 4 Completed Treatment Febrile Neutropenia / Haematological Malignancies 1 4 Completed Treatment Infection / Pneumonia 1 4 Completed Treatment Intra-Abdominal Infections 1 4 Unknown Status Treatment Methicillin-Resistant Staphylococcus Aureus (MRSA) / Ventilator-associated Bacterial Pneumonia / Ventilator-Associated Pneumonia (VAP) 1 3 Completed Treatment Abscesses / Cellulitis / Skin Infections 1 3 Completed Treatment Bacterial Infections 1 3 Completed Treatment Complicated Intra-Abdominal Infections / Complicated Urinary Tract Infection 1 3 Completed Treatment Pneumonia, Bacterial 2 3 Recruiting Treatment Illness, Critical / Resistant Infection / Traumas 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intravenous 500 mg Powder Not applicable 1 kg/1kg Injection Intravenous 250 mg Injection, powder, for solution 500 mg Injection, powder, for solution Intravenous 0.5 g Injection, powder, for suspension Intravenous 500 MG Injection, powder, for solution Parenteral 500 mg Injection, powder, for solution Intravenous 250 mg Powder, for solution Intravenous Injection, powder, for suspension Intramuscular Injection, powder, for solution Intravenous Powder, for solution Intravenous 500 MG Injection Intravenous 500 mg Injection, powder, for solution 560 mg Injection, powder, for suspension Intravenous 250 MG Injection, powder, for suspension Intravenous 500 MG/100ML Injection, powder, for suspension Intravenous 500 MG/2ML Injection, powder, for solution Intravenous 500 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region Unlock Additional DataUS8487093 No 2013-07-16 2029-11-19 US Additional Data Available- Filed OnFiled OnAvailable for Purchase
The date on which a patent was filed with the relevant government.
Learn more
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 655.5 ChemSpider: Cilastatin - Predicted Properties
Property Value Source Water Solubility 0.1 mg/mL ALOGPS logP -0.29 ALOGPS logP -1.3 ChemAxon logS -3.6 ALOGPS pKa (Strongest Acidic) 2.53 ChemAxon pKa (Strongest Basic) 9.14 ChemAxon Physiological Charge -1 ChemAxon Hydrogen Acceptor Count 6 ChemAxon Hydrogen Donor Count 4 ChemAxon Polar Surface Area 129.72 Å2 ChemAxon Rotatable Bond Count 11 ChemAxon Refractivity 92.85 m3·mol-1 ChemAxon Polarizability 38.28 Å3 ChemAxon Number of Rings 1 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.8691 Blood Brain Barrier - 0.5892 Caco-2 permeable - 0.6738 P-glycoprotein substrate Substrate 0.8165 P-glycoprotein inhibitor I Non-inhibitor 0.7489 P-glycoprotein inhibitor II Non-inhibitor 0.9872 Renal organic cation transporter Non-inhibitor 0.9504 CYP450 2C9 substrate Non-substrate 0.8178 CYP450 2D6 substrate Non-substrate 0.8169 CYP450 3A4 substrate Non-substrate 0.5118 CYP450 1A2 substrate Non-inhibitor 0.8369 CYP450 2C9 inhibitor Non-inhibitor 0.8179 CYP450 2D6 inhibitor Non-inhibitor 0.9002 CYP450 2C19 inhibitor Non-inhibitor 0.76 CYP450 3A4 inhibitor Non-inhibitor 0.7213 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9653 Ames test Non AMES toxic 0.7689 Carcinogenicity Non-carcinogens 0.9312 Biodegradation Not ready biodegradable 0.9424 Rat acute toxicity 2.3144 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9946 hERG inhibition (predictor II) Non-inhibitor 0.9675
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Zinc ion binding
- Specific Function
- Hydrolyzes a wide range of dipeptides. Implicated in the renal metabolism of glutathione and its conjugates. Converts leukotriene D4 to leukotriene E4; it may play an important role in the regulati...
- Gene Name
- DPEP1
- Uniprot ID
- P16444
- Uniprot Name
- Dipeptidase 1
- Molecular Weight
- 45673.48 Da
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
- Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
- Farrell CA, Allegretto NJ, Hitchcock MJ: Cilastatin-sensitive dehydropeptidase I enzymes from three sources all catalyze carbapenem hydrolysis and conversion of leukotriene D4 to leukotriene E4. Arch Biochem Biophys. 1987 Jul;256(1):253-9. [PubMed:3038022]
- Kumon H, Nasu Y, Ohmori H, Kodama H, Konishi Y: [Effects of cilastatin sodium, an inhibitor of dehydropeptidase-I, on human urinary peptide excretion. Patients with renal insufficiency]. Jpn J Antibiot. 1987 Sep;40(9):1571-83. [PubMed:3480361]
- Lin JH, Chen IW, Ulm EH: Dose-dependent kinetics of cilastatin in laboratory animals. Drug Metab Dispos. 1989 Jul-Aug;17(4):426-32. [PubMed:2571484]
- Richerson MA, Ambrose PG, Quintiliani R, Nightingale CH: Formulary review of the carbapenems: comparison of imipenem/cilastatin and meropenem. Conn Med. 1998 Mar;62(3):165-9. [PubMed:9573653]
- Hirota T, Nishikawa Y, Tanaka M, Igarashi T, Kitagawa H: Characterization of dehydropeptidase I in the rat lung. Eur J Biochem. 1986 Nov 3;160(3):521-5. [PubMed:3780719]
- Hirota T, Nishikawa Y, Komai T, Igarashi T, Kitagawa H: Role of dehydropeptidase-I in the metabolism of glutathione and its conjugates in the rat kidney. Res Commun Chem Pathol Pharmacol. 1987 May;56(2):235-42. [PubMed:3474745]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
- Keynan S, Hooper NM, Felici A, Amicosante G, Turner AJ: The renal membrane dipeptidase (dehydropeptidase I) inhibitor, cilastatin, inhibits the bacterial metallo-beta-lactamase enzyme CphA. Antimicrob Agents Chemother. 1995 Jul;39(7):1629-31. [PubMed:7492120]
- FDA: Recarbrio Label [Link]
- FDA: Primaxin Label [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
- Gene Name
- SLC22A6
- Uniprot ID
- Q4U2R8
- Uniprot Name
- Solute carrier family 22 member 6
- Molecular Weight
- 61815.78 Da
References
- Takeda M, Narikawa S, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of organic anion transport inhibitors using cells stably expressing human organic anion transporters. Eur J Pharmacol. 2001 May 11;419(2-3):113-20. [PubMed:11426832]
- Khamdang S, Takeda M, Shimoda M, Noshiro R, Narikawa S, Huang XL, Enomoto A, Piyachaturawat P, Endou H: Interactions of human- and rat-organic anion transporters with pravastatin and cimetidine. J Pharmacol Sci. 2004 Feb;94(2):197-202. [PubMed:14978359]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
- Gene Name
- SLC22A8
- Uniprot ID
- Q8TCC7
- Uniprot Name
- Solute carrier family 22 member 8
- Molecular Weight
- 59855.585 Da
References
- Takeda M, Narikawa S, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of organic anion transport inhibitors using cells stably expressing human organic anion transporters. Eur J Pharmacol. 2001 May 11;419(2-3):113-20. [PubMed:11426832]
- Khamdang S, Takeda M, Shimoda M, Noshiro R, Narikawa S, Huang XL, Enomoto A, Piyachaturawat P, Endou H: Interactions of human- and rat-organic anion transporters with pravastatin and cimetidine. J Pharmacol Sci. 2004 Feb;94(2):197-202. [PubMed:14978359]
Drug created on June 13, 2005 07:24 / Updated on June 13, 2020 10:24