β-lactam antibiotic; bacerial cell wall synthesis; dehydropeptidase I

Combination of imipenem and cilastatin that is used in the treatment of bacterial infections; cilastatin inhibits renal dehydropeptidase I to prolong the half-life and increase the tissue penetration of imipenem, enhancing its efficacy as an anti-bacterial agent.

The bactericidal activity of imipenem results from the inhibition of cell wall synthesis. Its greatest affinity is for penicillin binding proteins (PBPs) 1A, 1B, 2, 4, 5 and 6 of Escherichia coli, and 1A, 1B, 2, 4 and 5 of Pseudomonas aeruginosa. The lethal effect is related to binding to PBP 2 and PBP 1B. Imipenem has a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria. It is a potent inhibitor of betalactamases from certain gram-negative bacteria which are inherently resistant to most beta-lactam antibiotics, e.g., Pseudomonas aeruginosa, Serratia spp., and Enterobacter spp. Imipenem has in vitro activity against a wide range of gram-positive and gram-negative organisms. Imipenem has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections treated with the intravenous formulation of imipenem-cilastatin sodium[1].

The dosage recommendations for PRIMAXIN I.V. represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution. Each 125 mg, 250 mg, or 500 mg dose should be given by intravenous administration over 20 to 30 minutes. Each 750 mg or 1000 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed. The total daily dosage for PRIMAXIN I.V. should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s), renal function, and body weight. Adult patients with impaired renal function, as judged by creatinine clearance ≤70 mL/min/1.73 m2, require adjustment of dosage as described in the succeeding section of these guidelines. Intravenous Dosage Schedule for Adults with Normal Renal Function and Body Weight ≥70 kg Doses cited in Table I are based on a patient with normal renal function and a body weight of 70 kg. These doses should be used for a patient with a creatinine clearance of ≥71 mL/min/1.73 m2 and a body weight of ≥70 kg. A reduction in dose must be made for a patient with a creatinine clearance of ≤70 mL/min/1.73 m2 and/or a body weight less than 70 kg. (See Tables II and III.) Dosage regimens in column A of Table I are recommended for infections caused by fully susceptible organisms which represent the majority of pathogenic species. Dosage regimens in column B of Table I are recommended for infections caused by organisms with moderate susceptibility to imipenem, primarily some strains of P. aeruginosa.[1]

Twenty minutes after intravenous infusion of PRIMAXIN IV, peak plasma concentrations of imipenem were 14 to 24 µg/mL at a dose of 250 mg, 21 to 58 µg/mL at a dose of 500 mg, and 41 to 83 µg/mL at a dose of 1000 mg. At these doses, plasma concentrations of imipenem decreased to below 1 µg/mL within 4 to 6 hours. Twenty minutes after intravenous infusion of PRIMAXIN IV, peak plasma concentrations of cilastatin were 15 to 25 µg/mL at a dose of 250 mg, 31 to 49 µg/mL at a dose of 500 mg, and 56 to 88 µg/mL at a dose of 1000 mg. The plasma half-life of each component was approximately 1 hour. Imipenem bound to human serum proteins by approximately 20%, and cilastatin bound by approximately 40%. Approximately 70% of imipenem is excreted in the urine within 10 hours after administration, after which imipenem excretion is no longer detectable in the urine. Following administration of a 500 mg dose of primesartan IV (PRIMAXIN IV), urinary imipenem concentrations can be maintained above 10 µg/mL for up to 8 hours. Approximately 70% of the dose of cilastatin sodium is excreted in the urine within 10 hours after intravenous injection. In patients with normal renal function, no accumulation of imipenem/cilastatin in plasma or urine was observed even with administration every 6 hours. In healthy elderly volunteers (65 to 75 years of age, with age-appropriate renal function), the pharmacokinetics of a single intravenous injection of 500 mg imipenem and 500 mg cilastatin (administered over 20 minutes) were consistent with the expected pharmacokinetics in patients with mild renal impairment, therefore no dose adjustment was required. The mean plasma half-lives of imipenem and cilastatin were 91 ± 7.0 minutes and 69 ± 15 minutes, respectively. Multiple dosing had no effect on the pharmacokinetics of imipenem or cilastatin, and no accumulation of imipenem/cilastatin was observed. When used alone, imipenem is metabolized in the kidneys by dehydropeptidase I, resulting in relatively low drug concentrations in the urine. Cilastatin sodium is an inhibitor of this enzyme, effectively preventing the renal metabolism of imipenem; therefore, when imipenem and cilastatin sodium are administered concurrently, adequate antibacterial levels of imipenem are achieved in the urine.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Limited information suggests that imipenem's concentration in breast milk is low and is 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. Imipenem-cilastatin and imipenem-cilastatin-rebactam are available for use 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.

https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050587s065,050630s028lbl.pdf

The combination of imipenem and cilastatin is used to treat bacterial infections; cilastatin inhibits renal dehydropeptidase I, prolongs the half-life of imipenem and increases its tissue permeability, thereby enhancing its efficacy as an antibacterial agent.

C12H17N3O4S.C16H25N2NAO5S.H2O

697.80

657.25

92309-29-0

85960-17-4 (hydrochloride salt)

17756656

Typically exists as solid at room temperature

655.5ºC at 760mmHg

1.377

7

13

17

44

1010

5

CC1(C)C[C@@H]1C(=N/C(=C\CCCCSC[C@@H](C(=O)O)N)/C(=O)O)[O-].C[C@H]([C@H]1[C@H]2CC(=C(C(=O)O)N2C1=O)SCCNC=N)O.[Na+].O

NCCJWSXETVVUHK-ZYSAIPPVSA-N

InChI=1S/C16H26N2O5S.C12H17N3O4S/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;1-6(16)9-7-4-8(20-3-2-14-5-13)10(12(18)19)15(7)11(9)17/h6,10-11H,3-5,7-9,17H2,1-2H3,(H,18,19)(H,20,21)(H,22,23);5-7,9,16H,2-4H2,1H3,(H2,13,14)(H,18,19)/b12-6-;/t10-,11+;6-,7-,9-/m11/s1

(Z)-7-[(2R)-2-amino-2-carboxyethyl]sulfanyl-2-[[(1S)-2,2-dimethylcyclopropanecarbonyl]amino]hept-2-enoic acid;(5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

92309-29-0; Imipenem and cilastatin; Imipenem-Cilastatin sodium hydrate; (Z)-7-[(2R)-2-amino-2-carboxyethyl]sulfanyl-2-[[(1S)-2,2-dimethylcyclopropanecarbonyl]amino]hept-2-enoic acid;(5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid; Thienam; imipenem - cilastatin; Tienam 500; Tainem;

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.)