Identification

Name
Cilastatin
Accession Number
DB01597  (EXPT00918)
Type
Small Molecule
Groups
Approved, Investigational
Description

A renal dehydropeptidase-I and leukotriene D4 dipeptidase inhibitor. 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 increase its effectiveness. The drug also inhibits the metabolism of leukotriene D4 to leukotriene E4.

Structure
Thumb
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
Product Ingredients
IngredientUNIICASInChI Key
Cilastatin sodium5428WXZ74M81129-83-1QXPBTTUOVWMPJN-QBNHLFMHSA-M
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Imipenem and CilastatinCilastatin sodium (250 mg/100mL) + Imipenem monohydrate (250 mg/100mL)Injection, powder, for solutionIntravenousHospira, Inc.2011-11-16Not applicableUs
Imipenem and CilastatinCilastatin sodium (250 mg/20mL) + Imipenem monohydrate (250 mg/20mL)Injection, powder, for solutionIntravenousFresenius Kabi2012-01-03Not applicableUs
Imipenem and CilastatinCilastatin sodium (500 mg/1) + Imipenem monohydrate (500 mg/1)Injection, powder, for solutionIntravenousCardinal Health2012-01-032018-07-09Us
Imipenem and CilastatinCilastatin sodium (500 mg/100mL) + Imipenem monohydrate (500 mg/100mL)Injection, powder, for solutionIntravenousHospira, Inc.2011-11-16Not applicableUs
Imipenem and CilastatinCilastatin sodium (500 mg/20mL) + Imipenem monohydrate (500 mg/20mL)Injection, powder, for solutionIntravenousFresenius Kabi2012-01-03Not applicableUs
Imipenem and Cilastatin for InjectionCilastatin (250 mg) + Imipenem (250 mg)Powder, for solutionIntravenousPfizerNot applicableNot applicableCanada
Imipenem and Cilastatin for InjectionCilastatin (500 mg) + Imipenem (500 mg)Powder, for solutionIntravenousPfizer2011-05-02Not applicableCanada
Imipenem and Cilastatin for Injection USPCilastatin (500 mg) + Imipenem (500 mg)Powder, for solutionIntravenousSandoz Canada Incorporated2010-12-21Not applicableCanada
Imipenem and Cilastatin for Injection USPCilastatin (250 mg) + Imipenem (250 mg)Powder, for solutionIntravenousSandoz Canada Incorporated2010-12-21Not applicableCanada
Imipenem and Cilastatin for Injection, USPCilastatin (250 mg) + Imipenem (250 mg)Powder, for solutionIntravenousMethapharm, Inc.Not applicableNot applicableCanada
Categories
UNII
141A6AMN38
CAS number
82009-34-5
Weight
Average: 358.453
Monoisotopic: 358.156242642
Chemical Formula
C16H26N2O5S
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

Pharmacology

Indication

Combined intravenously with imipenem in order to protect it from dehydropeptidase and prolong its antibacterial effect.

Associated Conditions
Pharmacodynamics

Cilastatin is a chemical compound which inhibits the human enzyme dehydropeptidase. Dehydropeptidase is found in the kidney and is responsible for degrading 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.

Mechanism of action

Cilastatin is a specific and reversible renal dehydropeptidase-I inhibitor. 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 and thus the inactivation of imipenem so that antibacterial levels of imipenem can be attained in the urine. The drug also prevents the metabolism of leukotriene D4 to leukotriene E4 through the inhibition of leukotriene D4 dipeptidase.

TargetActionsOrganism
ADipeptidase 1
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcyclovirThe excretion of Acyclovir can be decreased when combined with Cilastatin.
Adefovir DipivoxilThe excretion of Adefovir Dipivoxil can be decreased when combined with Cilastatin.
AllopurinolThe excretion of Allopurinol can be decreased when combined with Cilastatin.
AlprostadilThe excretion of Alprostadil can be decreased when combined with Cilastatin.
Aminohippuric acidThe excretion of Aminohippuric acid can be decreased when combined with Cilastatin.
AvibactamThe excretion of Avibactam can be decreased when combined with Cilastatin.
BaricitinibThe excretion of Baricitinib can be decreased when combined with Cilastatin.
BenzylpenicillinThe excretion of Benzylpenicillin can be decreased when combined with Cilastatin.
BumetanideThe excretion of Bumetanide can be decreased when combined with Cilastatin.
CaptoprilThe excretion of Captopril can be decreased when combined with Cilastatin.
Food Interactions
Not Available

References

Synthesis Reference

Yatendra Kumar, "Process for the preparation of amorphous cilastatin sodium." U.S. Patent US20040152780, issued August 05, 2004.

US20040152780
General References
  1. 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]
External Links
Human Metabolome Database
HMDB0015535
KEGG Drug
D07698
KEGG Compound
C01675
PubChem Compound
6435415
PubChem Substance
46505611
ChemSpider
4940183
BindingDB
50367502
ChEBI
3697
ChEMBL
CHEMBL766
Therapeutic Targets Database
DAP000632
PharmGKB
PA448998
HET
CIL
Wikipedia
Cilastatin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedOtherDose Finding Study1
1CompletedTreatmentInfectious Diseases1
1RecruitingTreatmentAcinetobacter Baumannii Infection1
2CompletedTreatmentAbdominal Abscess / Bacterial Infections / Pneumonia / Pneumonia, Bacterial / Ventilator-Associated Pneumonia (VAP)1
2CompletedTreatmentComplicated Urinary Tract Infections1
2CompletedTreatmentPyelonephritis / Urinary Tract Infections (UTIs)1
2CompletedTreatmentUrinary Tract Infections (UTIs)1
2TerminatedTreatmentPneumonia, Bacterial1
2TerminatedTreatmentUrinary Tract Infections (UTIs)1
3CompletedTreatmentAbscesses / Cellulitis / Skin-structure infections1
3CompletedTreatmentBacterial Infections1
3CompletedTreatmentComplicated Intra-Abdominal Infections / Complicated Urinary Tract Infections1
3CompletedTreatmentPneumonia, Bacterial1
3RecruitingTreatmentPneumonia, Bacterial1
4CompletedTreatmentIntra-Abdominal Infections1
4Unknown StatusTreatmentMethicillin-Resistant Staphylococcus Aureus (MRSA) / Ventilator-Associated Pneumonia (VAP)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, for solutionIntravenous
Powder, for solutionIntravenous
Injection, powder, for suspensionIntramuscular
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.1 mg/mLALOGPS
logP-0.29ALOGPS
logP-1.3ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)2.53ChemAxon
pKa (Strongest Basic)9.14ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area129.72 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity92.85 m3·mol-1ChemAxon
Polarizability38.28 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8691
Blood Brain Barrier-0.5892
Caco-2 permeable-0.6738
P-glycoprotein substrateSubstrate0.8165
P-glycoprotein inhibitor INon-inhibitor0.7489
P-glycoprotein inhibitor IINon-inhibitor0.9872
Renal organic cation transporterNon-inhibitor0.9504
CYP450 2C9 substrateNon-substrate0.8178
CYP450 2D6 substrateNon-substrate0.8169
CYP450 3A4 substrateNon-substrate0.5118
CYP450 1A2 substrateNon-inhibitor0.8369
CYP450 2C9 inhibitorNon-inhibitor0.8179
CYP450 2D6 inhibitorNon-inhibitor0.9002
CYP450 2C19 inhibitorNon-inhibitor0.76
CYP450 3A4 inhibitorNon-inhibitor0.7213
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9653
Ames testNon AMES toxic0.7689
CarcinogenicityNon-carcinogens0.9312
BiodegradationNot ready biodegradable0.9424
Rat acute toxicity2.3144 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9946
hERG inhibition (predictor II)Non-inhibitor0.9675
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QTOF , negativeLC-MS/MSsplash10-0a4i-0009000000-ef2198c6225f95e6b765
LC-MS/MS Spectrum - LC-ESI-QTOF , negativeLC-MS/MSsplash10-004i-0092000000-f0483d6314128c99a866
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-03fr-0089000000-e23865517b151264287c
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-0a4i-0009000000-f94440db25517ee87789
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-004i-0193000000-9c52bb64f789ddf44d03
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-01t9-0890000000-a16bc40171fdaad5d00f
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-01q9-0900000000-7f6fb4bc2c8d8b74669a
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-001i-0900000000-f7395a558e6db43df825
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-0a4i-0009000000-65b5dae5f837cb16f232
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-004i-0093000000-f41454497f85c6c231e3
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-004i-0890000000-2d4e1ce343461b9c33ff
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-001i-0900000000-f7395a558e6db43df825
LC-MS/MS Spectrum - LC-ESI-ITFT , negativeLC-MS/MSsplash10-03fr-0079000000-f5a7ea868a31218529fb
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0a4i-0009000000-afc7a1706de335756516
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0uxr-0292000000-fc9fdc71c26de516aa47
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0f89-0980000000-c7e9f3733dc9d5876f69
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0f89-0940000000-5e461031ed3e8be30dce
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0udl-0197000000-ed9524572e0f6a20cf73
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-0009000000-92adcd25c03169bce114
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-9350000000-49e92e77b9da299b75c9
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-9100000000-93ce7c9a2d2ddb232af8
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-9100000000-a5fb73965dbd68cad5ca
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-9000000000-314ddc83e7521820bbfc
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-9000000000-f4a4b127adc8552d8fff
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-0009000000-ee64e7f7019c68d1b37c
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-9340000000-52a3fa17dbbe9e3a1655
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-9100000000-455b80c43f8c12b3f0fc
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-9000000000-07045a080f03625d01af
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0002-9000000000-8832abb1f60cae723d4a
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00kb-9000000000-92b4d4d580bdc8669cd2
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0udl-0197000000-a5c912d56f6b1064113a

Taxonomy

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
N-acyl-alpha-amino acid / L-cysteine-s-conjugate / Cysteine or derivatives / Alpha-amino acid / L-alpha-amino acid / Medium-chain fatty acid / Cyclopropanecarboxylic acid or derivatives / Dicarboxylic acid or derivatives / Unsaturated fatty acid / Fatty acid
show 21 more
Molecular Framework
Aliphatic homomonocyclic compounds
External Descriptors
non-proteinogenic L-alpha-amino acid, L-cysteine derivative, organic sulfide, carboxamide (CHEBI:3697)

Targets

Kind
Protein
Organism
Human
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  10. 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]

Transporters

Kind
Protein
Organism
Human
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
  1. 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]
  2. 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
Human
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
  1. 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]
  2. 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 December 14, 2018 12:40