Doripenem
Identification
- Summary
Doripenem is an antibiotic of the penem class used to treat complicated intra-abdominal and urinary tract infections.
- Generic Name
- Doripenem
- DrugBank Accession Number
- DB06211
- Background
Doripenem is a broad-spectrum, carbapenem antibiotic marketed under the brand name Doribax by Janssen. Doripenem injection was approved by the FDA in 2007 to treat complicated urinary tract and intra-abdominal infections. In a clinical trial of doripenem treatment in ventilator associated pneumonia (vs. imipenem and cilastatin), it was found that doripenem carried an increased risk of death and lower clinical cure rates, resulting in a premature termination of the trial. The FDA revised the doripenem label in 2014 to include a warning against use in ventilator-associated pneumonia and to reiterate its safety and efficacy for its approved indications.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 420.504
Monoisotopic: 420.1137259 - Chemical Formula
- C15H24N4O6S2
- Synonyms
- Doripenem
- External IDs
- S 4661
- S-4661
Pharmacology
- Indication
Doripenem is indicated in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis, caused by designated susceptible bacteria.
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- Pharmacodynamics
Similar to other beta-lactam antimicrobial agents, the time that unbound plasma concentration of doripenem exceeds the MIC (T>MIC) of the infecting organism has been shown to best correlate with efficacy in animal models of infection.
- Mechanism of action
Doripenem is a broad-spectrum carbapenem antibiotic with activity against many gram-positive and gram-negative aerobic bacteria, as well as a variety of anaerobes. Like other beta-lactam antibiotics, doripenem's bactericidal mechanism of action is mostly due to cell death after inhibition of bacterial enzymes called penicillin-bindng proteins (PBPs), which are responsible for peptidoglycan cross-linking during the synthesis of the bacterial cell wall. Carbapenems mainly have high affinity for PBPs 1a, 1b, 2 and 3. Inhibition of each PBP usually results in a different inactivating mechanism. Inhibition of PBPs 1a and 1b results in fast bacterial killing through the formation of spheroplasts, inhibition of PBP 2 results in rod-shaped bacteria to become spherical, and inhibition of PBP 3 results in filamentous-shaped organisms. The PBPs preferentially bound by different carbapenems depend on the organism. In E.coli and P.aeruginosa, doripenem binds to PBP 2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4. Doripenem has a 1-beta-methyl side chain, which allows it to be relatively resistant to dehydropeptidase, as well as a trans-alpha-1-hydroxyethyl group at position 6 which provides beta-lactamase resistance. Like other carbapenems, doripenem is different from most beta-lactams due to its stability against hydrolysis by most beta-lactamases, including penicillinases, cephalosporinases, ESBL, and Amp-C producing enterobacteriaceae.
Target Actions Organism APenicillin-binding protein 1A antagonistinhibitorEscherichia coli (strain K12) APenicillin-binding protein 1B antagonistinhibitorEscherichia coli (strain K12) APenicillin-binding protein 2 antagonistinhibitorEscherichia coli (strain K12) APenicillin-binding protein 3 antagonistinhibitorPseudomonas aeruginosa APenicillin-binding protein 4 antagonistinhibitorStaphylococcus aureus - Absorption
Doripenem is administered intravenously as an infusion. There was no accumulation of doripenem following mulitiple infusions of either 500mg or 1g administered every 8 hours for 7-10 days in subjects with normal renal function.
- Volume of distribution
The average Vd is 16.8 L (8.09-55.5 L) at steady-state in healthy subjects. Doripenem penetrates into many tissues and fluids, including potential sites of approved indication infections.
- Protein binding
8.1%
- Metabolism
Metabolism of doripenem is via dehydropeptidase-I (also called dipeptidase-1) into a microbiologically inactive ring-opened metabolite, doripenem-M1. Doripenem does not appear to be a substrate of the hepatic CYP450 enzymes.
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- Route of elimination
Doripenem is primarily eliminated unchanged by the kidneys and undergoes glomerular filtration and active tubular secretion. A mean of 71% and 15% of the dose was recovered in urine as unchanged drug and the ring-opened metabolite, respectively, within 48 hours of 500 mg dose in healthy adults. Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy adults, less than 1% of the total radioactivity was recovered in feces after one week.
- Half-life
1 hour, in healthy non-elderly adults.
- Clearance
10.3 L/hour.
- Adverse Effects
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- Toxicity
Dosage adjustment is necessary in patients with moderate and severe renal impairment.
Doripenem's FDA label includes a warning against use in ventilator-associated bacterial pneumonia, as a clinical trial for that indication resulted in increased mortality with doripenem (23% vs. 16.7% recieving imipenem) as well as lower clinical response rates.
Seizures have been reported with doripenem treatment; patients at greater risk of developing seizures we found to have pre-existing central nervous system (CNS) conditions, compromised renal function, or patients receiving higher doses than 500 mg every 8 hours. Doripenem also reduces plasma levels of valproic acid when administered concomitantly; therefore patients with pre-existing seizure disorders on valproic acid are at even higher risk of breakthrough seizures if receiving both drugs at the same time.
Doripenem is considered pregnancy category B as it was not found to be teratogenic or produce effects on ossification, developmental delays, or fetal weight in rat and rabbit studies. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. It is not known whether doripenem is excreted into breast milk, therefore caution should be exercised with doripenem administration to nursing women.
- 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 Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Doripenem which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Doripenem which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Doripenem which could result in a higher serum level. Acenocoumarol The risk or severity of bleeding can be increased when Doripenem is combined with Acenocoumarol. Acetaminophen Acetaminophen may decrease the excretion rate of Doripenem which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Doripenem which could result in a lower serum level and potentially a reduction in efficacy. Acetylsalicylic acid The excretion of Doripenem can be decreased when combined with Acetylsalicylic acid. Aclidinium Doripenem may decrease the excretion rate of Aclidinium which could result in a higher serum level. Acrivastine Doripenem may decrease the excretion rate of Acrivastine which could result in a higher serum level. Acyclovir The excretion of Doripenem can be decreased when combined with Acyclovir. Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Doripenem hydrate 4B035T6NKT 364622-82-2 NTUBEBXBDGKBTJ-WGLOMNHJSA-N - International/Other Brands
- Finibax (Shionogi Co.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Doribax Injection, powder, for solution 500 mg Intravenous Janssen Cilag International Nv 2016-09-08 2014-10-17 EU Doribax Powder, for solution 500 mg/10mL Intravenous Janssen Pharmaceuticals 2007-10-12 2014-07-30 US Doribax Powder, for solution 500 mg / vial Intravenous Janssen Pharmaceuticals 2009-10-19 2013-07-03 Canada Doribax Powder, for solution 500 mg/10mL Intravenous Ortho-McNeil-Janssen Pharmaceuticals Inc. 2007-10-12 2011-02-28 US Doribax Injection, powder, for solution 250 mg Intravenous Janssen Cilag International Nv 2016-09-08 2014-10-17 EU Doribax Powder, for solution 500 mg/10mL Intravenous SHIONOGI INC. 2007-10-12 2020-02-28 US Doribax Powder, for solution 250 mg/10mL Intravenous SHIONOGI INC. 2010-10-15 2020-02-28 US Doribax Powder, for solution 250 mg/10mL Intravenous Janssen Pharmaceuticals 2010-10-15 2014-07-30 US Doripenem Powder, for solution 500 mg/10mL Intravenous Apotex Corp. 2016-12-05 2019-08-31 US Doripenem Powder, for solution 250 mg/10mL Intravenous Apotex Corp. 2016-12-05 2019-07-31 US
Categories
- ATC Codes
- J01DH04 — Doripenem
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as thienamycins. These are beta-lactam antibiotics that differ from penicillins in having the thiazolidine sulfur atom replaced by carbon, the sulfur then becoming the first atom in the side chain.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Lactams
- Sub Class
- Beta lactams
- Direct Parent
- Thienamycins
- Alternative Parents
- Alpha amino acids and derivatives / Pyrroline carboxylic acids / Azepines / Vinylogous thioesters / Sulfuric acid diamides / Tertiary carboxylic acid amides / Pyrrolidines / Thioenol ethers / Secondary alcohols / Amino acids show 10 more
- Substituents
- Alcohol / Aliphatic heteropolycyclic compound / Alpha-amino acid or derivatives / Amine / Amino acid / Amino acid or derivatives / Azacycle / Azepine / Azetidine / Carbonyl group show 26 more
- Molecular Framework
- Aliphatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Various aerobic and anaerobic microorganisms
- Pseudomonas aeruginosa
- Streptococcus pneumoniae
- Haemophilus influenzae
- Escherichia coli
- Staphylococcus aureus
- Enterococcus faecalis
- Moraxella catarrhalis
- Acinetobacter
- Enterococcus faecium
- Klebsiella
- Enterobacter
- Streptococcus constellatus
- Proteus mirabilis
Chemical Identifiers
- UNII
- BHV525JOBH
- CAS number
- 148016-81-3
- InChI Key
- AVAACINZEOAHHE-VFZPANTDSA-N
- InChI
- InChI=1S/C15H24N4O6S2/c1-6-11-10(7(2)20)14(21)19(11)12(15(22)23)13(6)26-9-3-8(17-5-9)4-18-27(16,24)25/h6-11,17-18,20H,3-5H2,1-2H3,(H,22,23)(H2,16,24,25)/t6-,7-,8+,9+,10-,11-/m1/s1
- IUPAC Name
- (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-{[(3S,5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl]sulfanyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
- SMILES
- [H][C@]12[C@@H](C)C(S[C@@H]3CN[C@H](CNS(N)(=O)=O)C3)=C(N1C(=O)[C@]2([H])[C@@H](C)O)C(O)=O
References
- General References
- Jones RN, Huynh HK, Biedenbach DJ: Activities of doripenem (S-4661) against drug-resistant clinical pathogens. Antimicrob Agents Chemother. 2004 Aug;48(8):3136-40. [Article]
- Chahine EB, Ferrill MJ, Poulakos MN: Doripenem: a new carbapenem antibiotic. Am J Health Syst Pharm. 2010 Dec 1;67(23):2015-24. doi: 10.2146/ajhp090672. [Article]
- Dedhia HV, McKnight R: Doripenem: position in clinical practice. Expert Rev Anti Infect Ther. 2009 Jun;7(5):507-14. doi: 10.1586/eri.09.37. [Article]
- Matthews SJ, Lancaster JW: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Ther. 2009 Jan;31(1):42-63. doi: 10.1016/j.clinthera.2009.01.013. [Article]
- External Links
- Human Metabolome Database
- HMDB0041883
- KEGG Drug
- D03895
- PubChem Compound
- 73303
- PubChem Substance
- 310264862
- ChemSpider
- 66040
- BindingDB
- 50088382
- 119771
- ChEBI
- 135928
- ChEMBL
- CHEMBL491571
- ZINC
- ZINC000003922770
- PDBe Ligand
- O6P
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Doripenem
- PDB Entries
- 6p9c
- FDA label
- Download (868 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Not Available Healthy Subjects (HS) 1 4 Completed Not Available Ventilator Associated Bacterial Pneumonia (VABP) 1 4 Completed Treatment Bacterial Infections / Cross Infection / Infection / Intraabdominal Infections / Urinary Tract Infection / Ventilator Associated Bacterial Pneumonia (VABP) 1 4 Completed Treatment Febrile Neutropenia 1 4 Completed Treatment Pneumonia / Urinary Tract Infection / Ventilator Associated Bacterial Pneumonia (VABP) 1 4 Completed Treatment Sepsis 1 3 Completed Treatment Appendicitis / Bacterial Infections and Mycoses / Gallbladder Inflammation / Pancreatitis / Peritonitis 2 3 Completed Treatment Complicated Urinary Tract Infection (cUTI) Including Acute Pyelonephritis 2 3 Completed Treatment Pneumonia 1 3 Completed Treatment Pneumonia / Ventilators, Mechanical 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous Injection, powder, lyophilized, for solution Intravenous 500 mg Injection, powder, for solution Intravenous 250 mg Powder, for solution Intravenous Powder, for solution Intravenous 250 mg/10mL Powder, for solution Intravenous 500 mg/10mL Powder, for solution Intravenous 500 mg / vial Injection, powder, lyophilized, for suspension Intravenous 500 mg Injection, powder, for solution Intravenous 500 mg/1vial Injection, powder, lyophilized, for solution Intravenous 0.5 g Injection, powder, for solution Intravenous 500 mg Powder 500 mg/1vial - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US5317016 No 1994-05-31 2012-08-14 US CA2404703 No 2007-06-05 2021-03-30 Canada CA2076430 No 1997-12-23 2012-08-19 Canada US8247402 No 2012-08-21 2021-03-30 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 3.13 mg/mL ALOGPS logP -1.3 ALOGPS logP -5.6 Chemaxon logS -2.1 ALOGPS pKa (Strongest Acidic) 3.34 Chemaxon pKa (Strongest Basic) 9.51 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 8 Chemaxon Hydrogen Donor Count 5 Chemaxon Polar Surface Area 162.06 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 99.88 m3·mol-1 Chemaxon Polarizability 42.37 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption - 0.6542 Blood Brain Barrier - 0.9633 Caco-2 permeable - 0.6508 P-glycoprotein substrate Substrate 0.7634 P-glycoprotein inhibitor I Non-inhibitor 0.8733 P-glycoprotein inhibitor II Non-inhibitor 1.0 Renal organic cation transporter Non-inhibitor 0.9288 CYP450 2C9 substrate Non-substrate 0.7918 CYP450 2D6 substrate Non-substrate 0.8135 CYP450 3A4 substrate Non-substrate 0.6002 CYP450 1A2 substrate Non-inhibitor 0.8052 CYP450 2C9 inhibitor Non-inhibitor 0.7661 CYP450 2D6 inhibitor Non-inhibitor 0.8798 CYP450 2C19 inhibitor Non-inhibitor 0.7305 CYP450 3A4 inhibitor Non-inhibitor 0.9118 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9886 Ames test Non AMES toxic 0.6139 Carcinogenicity Non-carcinogens 0.6727 Biodegradation Not ready biodegradable 0.8469 Rat acute toxicity 2.4823 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9799 hERG inhibition (predictor II) Non-inhibitor 0.878
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets

- Kind
- Protein
- Organism
- Escherichia coli (strain K12)
- Pharmacological action
- Yes
- Actions
- AntagonistInhibitor
- General Function
- Serine-type d-ala-d-ala carboxypeptidase activity
- Specific Function
- Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan str...
- Gene Name
- mrcA
- Uniprot ID
- P02918
- Uniprot Name
- Penicillin-binding protein 1A
- Molecular Weight
- 93635.545 Da
References
- Matthews SJ, Lancaster JW: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Ther. 2009 Jan;31(1):42-63. doi: 10.1016/j.clinthera.2009.01.013. [Article]
- Kind
- Protein
- Organism
- Escherichia coli (strain K12)
- Pharmacological action
- Yes
- Actions
- AntagonistInhibitor
- General Function
- Serine-type d-ala-d-ala carboxypeptidase activity
- Specific Function
- Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan str...
- Gene Name
- mrcB
- Uniprot ID
- P02919
- Uniprot Name
- Penicillin-binding protein 1B
- Molecular Weight
- 94291.875 Da
References
- Matthews SJ, Lancaster JW: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Ther. 2009 Jan;31(1):42-63. doi: 10.1016/j.clinthera.2009.01.013. [Article]
- Kind
- Protein
- Organism
- Escherichia coli (strain K12)
- Pharmacological action
- Yes
- Actions
- AntagonistInhibitor
- General Function
- Serine-type d-ala-d-ala carboxypeptidase activity
- Specific Function
- Cell wall formation; PBP-2 is responsible for the determination of the rod shape of the cell. It synthesizes cross-linked peptidoglycan from lipid intermediates.
- Gene Name
- mrdA
- Uniprot ID
- P0AD65
- Uniprot Name
- Penicillin-binding protein 2
- Molecular Weight
- 70856.1 Da
References
- Matthews SJ, Lancaster JW: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Ther. 2009 Jan;31(1):42-63. doi: 10.1016/j.clinthera.2009.01.013. [Article]
- Kind
- Protein
- Organism
- Pseudomonas aeruginosa
- Pharmacological action
- Yes
- Actions
- AntagonistInhibitor
- General Function
- Peptidoglycan glycosyltransferase activity
- Specific Function
- Not Available
- Gene Name
- pbpB
- Uniprot ID
- Q51504
- Uniprot Name
- Cell division protein
- Molecular Weight
- 62855.78 Da
References
- Matthews SJ, Lancaster JW: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic. Clin Ther. 2009 Jan;31(1):42-63. doi: 10.1016/j.clinthera.2009.01.013. [Article]
- Kind
- Protein
- Organism
- Staphylococcus aureus
- Pharmacological action
- Yes
- Actions
- AntagonistInhibitor
- General Function
- Serine-type d-ala-d-ala carboxypeptidase activity
- Specific Function
- Not Available
- Gene Name
- pbp4
- Uniprot ID
- P72355
- Uniprot Name
- Penicillin-binding protein 4
- Molecular Weight
- 48237.14 Da
References
- Dedhia HV, McKnight R: Doripenem: position in clinical practice. Expert Rev Anti Infect Ther. 2009 Jun;7(5):507-14. doi: 10.1586/eri.09.37. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- Cirillo I, Mannens G, Janssen C, Vermeir M, Cuyckens F, Desai-Krieger D, Vaccaro N, Kao LM, Devineni D, Redman R, Turner K: Disposition, metabolism, and excretion of [14C]doripenem after a single 500-milligram intravenous infusion in healthy men. Antimicrob Agents Chemother. 2008 Oct;52(10):3478-83. doi: 10.1128/AAC.00424-08. Epub 2008 Jul 21. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- 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
- Greer ND: Doripenem (Doribax): the newest addition to the carbapenems. Proc (Bayl Univ Med Cent). 2008 Jul;21(3):337-41. [Article]
Drug created at March 19, 2008 16:17 / Updated at February 21, 2021 18:52