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Identification
NameCilastatin
Accession NumberDB01597  (EXPT00918)
TypeSmall Molecule
GroupsApproved
DescriptionA 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. [PubChem]
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
Cilastatina
Cilastatine
Cilastatinum
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
Imipenem and CilastatinCardinal Health
Imipenem and Cilastatin for InjectionHospira Healthcare Corporation
Imipenem and Cilastatin for Injection USPSandoz Canada Incorporated
Imipenem and Cilastatin for Injection, USPMethapharm Inc
Primaxin 250Merck Canada Inc
Primaxin 500Merck Canada Inc
Primaxin IVMerck Sharp & Dohme Corp.
Primaxin IV 250/250 Add-vantage VialMerck Frosst Canada & Cie, Merck Frosst Canada & Co.
Primaxin IV 500Merck Canada Inc
Ran-imipenem-cilastatinRanbaxy Pharmaceuticals Canada Inc.
Salts
Name/CASStructureProperties
Cilastatin sodium
ThumbNot applicableDBSALT001295
Categories
UNII141A6AMN38
CAS number82009-34-5
WeightAverage: 358.453
Monoisotopic: 358.156242642
Chemical FormulaC16H26N2O5S
InChI KeyInChIKey=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
N[C@@H](CSCCCC\C=C(/NC(=O)[[email protected]]1CC1(C)C)C(=O)O)C(=O)O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as n-acyl-aliphatic-alpha amino acids. These are alpha amino acids carrying a N-acylated aliphatic chain.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentN-acyl-aliphatic-alpha amino acids
Alternative Parents
Substituents
  • N-acyl-aliphatic-alpha amino acid
  • S-alkyl-l-cysteine
  • L-alpha-amino acid
  • Alpha-amino acid
  • Carbocyclic fatty acid
  • Medium-chain fatty acid
  • Amino fatty acid
  • Fatty acyl
  • Fatty acid
  • Unsaturated fatty acid
  • Dicarboxylic acid or derivatives
  • Cyclopropanecarboxylic acid or derivatives
  • Secondary carboxylic acid amide
  • Carboxamide group
  • Dialkylthioether
  • Sulfenyl compound
  • Thioether
  • Enamine
  • Carboxylic acid
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Primary amine
  • Organosulfur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Primary aliphatic amine
  • Carbonyl group
  • Amine
  • Aliphatic homomonocyclic compound
Molecular FrameworkAliphatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationCombined intravenously with imipenem in order to protect it from dehydropeptidase and prolong its antibacterial effect.
PharmacodynamicsCilastatin 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 actionCilastatin 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.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Powder for solutionintravenous
Injection, powder, for solutionintravenous
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.1 mg/mLALOGPS
logP-0.29ALOGPS
logP-1.3ChemAxon
logS-3.5ALOGPS
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 FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot 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
ATC CodesNot Available
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AbacavirThe serum concentration of Abacavir can be decreased when it is combined with Cilastatin.
AlfuzosinThe serum concentration of Alfuzosin can be increased when it is combined with Cilastatin.
AlprazolamThe serum concentration of Alprazolam can be increased when it is combined with Cilastatin.
AmineptineThe serum concentration of Amineptine can be increased when it is combined with Cilastatin.
AminophyllineThe serum concentration of Aminophylline can be decreased when it is combined with Cilastatin.
AmitriptylineThe serum concentration of Amitriptyline can be increased when it is combined with Cilastatin.
AtorvastatinThe serum concentration of Atorvastatin can be increased when it is combined with Cilastatin.
BoceprevirThe serum concentration of Cilastatin can be decreased when it is combined with Boceprevir.
BromocriptineThe serum concentration of Bromocriptine can be increased when it is combined with Cilastatin.
CabergolineThe serum concentration of Cabergoline can be increased when it is combined with Cilastatin.
CarbamazepineThe metabolism of Cilastatin can be increased when combined with Carbamazepine.
CisaprideThe serum concentration of Cisapride can be increased when it is combined with Cilastatin.
ClarithromycinThe therapeutic efficacy of Clarithromycin can be decreased when used in combination with Cilastatin.
ClomipramineThe serum concentration of Clomipramine can be increased when it is combined with Cilastatin.
CyclobenzaprineThe serum concentration of Cyclobenzaprine can be increased when it is combined with Cilastatin.
CyclophosphamideThe risk or severity of adverse effects can be increased when Cilastatin is combined with Cyclophosphamide.
CyclosporineThe serum concentration of Cyclosporine can be increased when it is combined with Cilastatin.
DelavirdineThe serum concentration of Delavirdine can be decreased when it is combined with Cilastatin.
DesipramineThe serum concentration of Desipramine can be increased when it is combined with Cilastatin.
DigoxinThe serum concentration of Digoxin can be increased when it is combined with Cilastatin.
DihydroergotamineThe serum concentration of Dihydroergotamine can be increased when it is combined with Cilastatin.
DosulepinThe serum concentration of Dosulepin can be increased when it is combined with Cilastatin.
DoxepinThe serum concentration of Doxepin can be increased when it is combined with Cilastatin.
DyphyllineThe serum concentration of Dyphylline can be decreased when it is combined with Cilastatin.
EnfuvirtideThe serum concentration of Enfuvirtide can be increased when it is combined with Cilastatin.
Ergoloid mesylateThe serum concentration of Ergoloid mesylate can be increased when it is combined with Cilastatin.
ErgonovineThe serum concentration of Ergonovine can be increased when it is combined with Cilastatin.
ErgotamineThe serum concentration of Ergotamine can be increased when it is combined with Cilastatin.
EsmirtazapineThe serum concentration of Esmirtazapine can be increased when it is combined with Cilastatin.
EtravirineThe serum concentration of Etravirine can be decreased when it is combined with Cilastatin.
GarlicThe serum concentration of Cilastatin can be decreased when it is combined with Garlic.
ImipramineThe serum concentration of Imipramine can be increased when it is combined with Cilastatin.
LovastatinThe serum concentration of Lovastatin can be increased when it is combined with Cilastatin.
MidazolamThe serum concentration of Midazolam can be increased when it is combined with Cilastatin.
MirtazapineThe serum concentration of Mirtazapine can be increased when it is combined with Cilastatin.
NefazodoneThe serum concentration of Nefazodone can be increased when it is combined with Cilastatin.
NortriptylineThe serum concentration of Nortriptyline can be increased when it is combined with Cilastatin.
PethidineThe risk or severity of adverse effects can be increased when Cilastatin is combined with Pethidine.
PimozideThe serum concentration of Pimozide can be increased when it is combined with Cilastatin.
ProtriptylineThe serum concentration of Protriptyline can be increased when it is combined with Cilastatin.
RiociguatThe serum concentration of Riociguat can be increased when it is combined with Cilastatin.
RosuvastatinThe serum concentration of Rosuvastatin can be increased when it is combined with Cilastatin.
SildenafilThe serum concentration of Sildenafil can be increased when it is combined with Cilastatin.
SimeprevirThe serum concentration of Simeprevir can be increased when it is combined with Cilastatin.
SimvastatinThe serum concentration of Simvastatin can be increased when it is combined with Cilastatin.
St. John's WortThe metabolism of Cilastatin can be increased when combined with St. John's Wort.
TacrolimusThe metabolism of Tacrolimus can be decreased when combined with Cilastatin.
TemsirolimusThe risk or severity of adverse effects can be increased when Cilastatin is combined with Temsirolimus.
TheophyllineThe serum concentration of Theophylline can be decreased when it is combined with Cilastatin.
TianeptineThe serum concentration of Tianeptine can be increased when it is combined with Cilastatin.
TipranavirThe serum concentration of Cilastatin can be decreased when it is combined with Tipranavir.
TriazolamThe serum concentration of Triazolam can be increased when it is combined with Cilastatin.
TrimipramineThe serum concentration of Trimipramine can be increased when it is combined with Cilastatin.
ZidovudineThe serum concentration of Zidovudine can be decreased when it is combined with Cilastatin.
Food InteractionsNot Available

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 regulation of leukotriene activity.
Gene Name:
DPEP1
Uniprot ID:
P16444
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 molecule of endogenous dicarboxylic acid (glutarate, ketoglutarate, etc). Mediates the sodium-independent uptake of 2,3-dimercapto-1-propanesulfonic acid (DMPS) (By similarity). Mediates the sodium-in...
Gene Name:
SLC22A6
Uniprot ID:
Q4U2R8
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, fexofenadine. Transports benzylpenicillin (PCG), estrone-3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA).
Gene Name:
SLC22A8
Uniprot ID:
Q8TCC7
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 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23