Penicillin-binding proteins (PBPs) [1,2]

- Broad-Spectrum Activity: Doripenem demonstrated potent activity against Gram-negative bacteria, including Pseudomonas aeruginosa and Enterobacteriaceae, with MIC90 values of ≤2 μg/mL for most strains. It also showed activity against Gram-positive pathogens like Staphylococcus aureus [1,2]
- β-Lactamase Stability: Resistant to hydrolysis by most β-lactamases, including extended-spectrum β-lactamases (ESBLs) and AmpC enzymes, due to its carbapenem ring structure [1,2]

- Efficacy in Murine Models: In a murine thigh infection model, doripenem administered intravenously at 10 mg/kg reduced bacterial load by >3 log10 CFU compared to untreated controls. Similar efficacy was observed in a rat model of peritoneal sepsis [2]
- Pharmacokinetic Profile: In healthy volunteers, doripenem exhibited a plasma half-life of 1.18 hours after intravenous administration, with 70-80% renal excretion as unchanged drug [2]

PBPs Binding Assay: 1. Membrane fractions from E. coli or P. aeruginosa were incubated with doripenem (0.01–10 μM) in Tris-HCl buffer (pH 7.5) at 37°C for 20 minutes. 2. Binding was detected via radiolabeled [³H]benzylpenicillin displacement, followed by SDS-PAGE and autoradiography. 3. Doripenem showed high affinity for PBP-2 and PBP-3, with IC50 values of 0.05 μM and 0.12 μM, respectively [2]

Bacterial Growth Inhibition: 1. P. aeruginosa strains (10⁶ CFU/mL) were exposed to doripenem (0.06–256 mg/L) in Mueller-Hinton broth. 2. MIC endpoints were determined after 24-hour incubation at 37°C. 3. Doripenem inhibited 90% of strains at ≤2 mg/L [1]

Murine Peritonitis Model: 1. ICR mice were infected intraperitoneally with E. coli (10⁹ CFU). 2. Doripenem (10–100 mg/kg) was administered intravenously every 8 hours for 3 days. 3. Survival rates were monitored for 7 days, with 100% survival at doses ≥50 mg/kg [2]

Absorption, Distribution and Excretion
Doripenum is administered via intravenous infusion. In subjects with normal renal function, no accumulation of doripenum was observed after intravenous infusion of 500 mg or 1 g every 8 hours for 7–10 days. Doripenum is primarily excreted unchanged via the kidneys, mainly through glomerular filtration and active tubular secretion. In healthy adults, mean 71% and 15% of the dose were recovered in urine within 48 hours after a 500 mg dose, respectively, with the unchanged drug and its open-ring metabolites being the open-ring metabolites. In healthy adults, less than 1% of the total radioactivity was recovered in feces one week after a single 500 mg dose of radiolabeled doripenum. The mean volume of distribution (Vd) at steady state in healthy subjects was 16.8 L (8.09–55.5 L). Doripenum can penetrate a variety of tissues and fluids, including potential sites of infection for its approved indications.
10.3 L/h.

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Metabolism/Metabolite
Doribenam is metabolized by dehydropeptidase-1 (also known as dipeptidase-1) to doribenam-M1, a microbially inactive open-ring metabolite. Doribenam does not appear to be a substrate of hepatic CYP450 enzymes.

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Biological half-life
In healthy, non-aged adults, it is 1 hour.

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- Plasma half-life: 1.18 hours in humans after intravenous infusion [2] - Renal excretion: Approximately 70-80% of the dose is excreted unchanged in the urine [2] - Protein binding: 8% in human plasma [2]

Hepatotoxicity
In patients receiving parenteral doribene for 5 to 14 days, 1% to 5% may experience mild, transient, asymptomatic elevations in serum transaminase levels. These abnormalities are usually self-limiting and asymptomatic, rarely exceeding 5 times the upper limit of normal. No cases of hepatitis with jaundice have been reported during the limited time doribene has been marketed. However, cholestatic jaundice has been reported during or shortly after treatment with other carbapenems. The incubation period is 1 to 3 weeks, and the pattern of enzyme elevation is usually cholestatic. Immune allergic reactions may occur, but autoantibodies are rare. The course is usually self-limiting, but at least one case of bile duct disappearance syndrome associated with carbapenems has been reported. Doribene and other carbapenems have not been found to be associated with cases of acute liver failure. Probability score: E (Unproven but suspected cause of liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information regarding the clinical use of doribenem during lactation. Its excretion in breast milk is likely similar to that of imipenem and meropenem, which have lower concentrations in breast milk and are not expected to have adverse effects on breastfed infants. There are reports that β-lactam antibiotics occasionally disrupt the infant's gut microbiota, leading to diarrhea or thrush, but these effects have not been fully assessed. Doribenem can be used in breastfeeding women.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding rate
8.1%

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- Central nervous system effects: In preclinical studies, doripenem induced seizures in rats at doses ≥200 mg/kg, likely due to its competitive binding to GABA receptors [2] - Renal safety: No significant nephrotoxicity was observed at therapeutic doses in animal studies [2]

[1]. J Antimicrob Chemother.2004 Jul;54(1):144-54;
[2]. Antimicrob Agents Chemother.2004 Aug;48(8):3136-40.

Doripenem is a carbapenem antibiotic. It is a broad-spectrum carbapenem antibiotic marketed by Johnson & Johnson under the brand name Doribax. Doripenem injection was approved by the U.S. Food and Drug Administration (FDA) in 2007 for the treatment of complicated urinary tract infections and intra-abdominal infections. In a clinical trial of Doripenem for ventilator-associated pneumonia (VAP) (compared to imipenem and cilastatin), Doripenem was found to increase the risk of death and reduce the clinical cure rate, leading to the early termination of the trial. The FDA revised the Doripenem label in 2014, adding a warning about its contraindication for VAP and reaffirming its safety and efficacy in its approved indications. Doripenem is a penem antibiotic. It is a broad-spectrum carbapenem antibiotic primarily used to treat aerobic Gram-negative bacterial infections. Like other carbapenem antibiotics, Doripenem can cause a transient and asymptomatic increase in serum enzymes. Carbapenem antibiotics have also been associated with rare, clinically significant cases of acute cholestatic liver injury. Doripenem is a broad-spectrum carbapenem antibiotic with bactericidal and anti-β-lactamase activity. Doripenem binds to penicillin-binding proteins (PBPs) located on the bacterial cell wall, particularly PBPs 2 and 3, thereby inhibiting the final transpeptidation step in the synthesis of peptidoglycan (an important component of the bacterial cell wall). This inhibition leads to weakening of the bacterial cell wall, ultimately resulting in cell wall lysis. The drug is 2 to 16 times more potent than imipenem and comparable to ertapenem and meropenem. It is a carbapenem derivative antibacterial drug that is more stable than imipenem and less susceptible to degradation by renal dehydropeptidase I, but does not require combination with enzyme inhibitors such as cilastatin. It is used to treat infections such as hospital-acquired pneumonia, complicated intra-abdominal infections, or urinary tract infections (including pyelonephritis).

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Drug Indications
Doripenem is indicated for the treatment of complicated intra-abdominal infections and complicated urinary tract infections (including pyelonephritis) caused by specified susceptible bacteria.
FDA Label
Doripenem is indicated for the treatment of the following infections in adults: hospital-acquired pneumonia (including ventilator-associated pneumonia); complicated intra-abdominal infections; complicated urinary tract infections. Official guidelines for the rational use of antimicrobial agents should be consulted.

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Mechanism of Action
Doripenem is a broad-spectrum carbapenem antibiotic active against a variety of Gram-positive and Gram-negative aerobic bacteria and a variety of anaerobic bacteria. Like other β-lactam antibiotics, Doripenem's bactericidal mechanism primarily involves cell death through inhibition of penicillin-binding protein (PBP) enzymes in bacteria. PBPs are responsible for the cross-linking of peptidoglycans during bacterial cell wall synthesis. Carbapenem antibiotics have a high affinity primarily for PBPs 1a, 1b, 2, and 3. Inhibition of each PBP typically results in a different inactivation mechanism. Inhibition of PBPs 1a and 1b leads to rapid bacterial death through the formation of spheroids; inhibition of PBP 2 causes rod-shaped bacteria to transform into spheroids; and inhibition of PBP 3 causes bacteria to transform into filaments. The PBPs that different carbapenem antibiotics preferentially bind to depend on the bacterial species. In Escherichia coli and Pseudomonas aeruginosa, domipenem binds to PBP 2 (involved in maintaining cell morphology) as well as PBPs 3 and 4. Doripenem possesses a 1-β-methyl side chain, making it relatively resistant to dehydropeptidases; furthermore, its trans-α-1-hydroxyethyl group at the 6-position makes it resistant to β-lactamases. Like other carbapenem antibiotics, domipenem differs from most β-lactam antibiotics in that it is stable against the hydrolysis of most β-lactamases, including penicillinase, cephalosporinase, and Enterobacteriaceae producing extended-spectrum β-lactamases (ESBLs) and AmpC enzymes.

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- Mechanism of action: Doripenum irreversibly inhibits penicillin-binding proteins (PBPs), disrupting peptidoglycan cross-links and leading to bacterial cell lysis [1,2]
- Clinical indications: Approved for the treatment of complicated intra-abdominal infections, urinary tract infections, and pneumonia caused by susceptible pathogens [1,2]
- Limitations: Lower activity against Enterococcus faecalis and Streptococcus pneumoniae compared to other carbapenems [1,2]

C15H24N4O6S2

420.5

420.113

C, 42.85; H, 5.75; N, 13.32; O, 22.83; S, 15.25

148016-81-3

Doripenem monohydrate;364622-82-2

73303

Off-white to light yellow solid powder

1.6±0.1 g/cm3

694.8±65.0 °C at 760 mmHg

>186ºC dec.

374.0±34.3 °C

0.0±4.9 mmHg at 25°C

1.681

-3.65

5

10

7

27

780

6

O=C(C(N12)=C(S[C@@H]3CN[C@H](CNS(=O)(N)=O)C3)[C@H](C)[C@]2([H])[C@@H]([C@H](O)C)C1=O)O

AVAACINZEOAHHE-VFZPANTDSA-N

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

(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

Doripenem; 148016-81-3; Doribax; S-4661; Finibax; BHV525JOBH; (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; DTXSID2046678;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)