β-lactam; cephalosporin antibiotic

Cefdinir, a new oral 2-amino-5-thiazolyl cephalosporin, inhibits the luminol-amplified chemiluminescence (LACL) response of human neutrophils stimulated by PMA but not opsonized zymosan, in a concentration-dependent but not time-dependent manner. Cefdinir inhibits LACL generation in cell-free systems consisting of H2O2, NaI, and either horseradish peroxidase or amyeloperoxidase-containing neutrophil extract. Cefdinir impairs LACL response induced by the calcium ionophore A23187 and FMLP, and this impairment is increased in cytochalasin B-treated neutrophils. Cefdinir directly inhibits the activity of myeloperoxidase-containing neutrophil extract released into the extracellular medium during neutrophil stimulation by soluble mediators, but has no effect on that released into the phagolysosome during phagocytosis. Cefdinir demonstrates excellent activity against a wide range of gram-positive and gram-negative bacteria. Cefdinir is resistant to a broad variety of β-lactamases and exhibits a β-lactam stability profile generally better than those observed with cefaclor and cefuroxime. Cefdinir elimination is primarily mediated by the kidney. Cefdinir interacts with the dipeptide transporters PEPT1 and PEPT2. Cefdinir tubular reabsorption is substantial, that Cefdinir tubular secretion is inhibitable by probenecid, and that this secretion is probably mediated by the renal organic anion secretory pathway.

Cefdinir (Omnicef; Abbott Laboratories) is a cephalosporin antibiotic primarily eliminated by the kidney. Nonlinear renal elimination of cefdinir has been previously reported. Cefdinir renal transport mechanisms were studied in the erythrocyte-free isolated perfused rat kidney. Studies were performed with drug-free perfusate and perfusate containing cefdinir alone to establish the baseline physiology and investigate cefdinir renal elimination characteristics. To investigate cefdinir renal transport mechanisms, inhibition studies were conducted by coperfusing cefdinir with inhibitors of the renal organic anion (probenecid), organic cation (tetraethylammonium), or dipeptide (glycylsarcosine) transport system. Cefdinir concentrations in biological samples were determined using reversed-phase high-performance liquid chromatography. Differences between treatments and controls were evaluated using analysis of variance and Dunnett's test. The excretion ratio (ER; the renal clearance corrected for the fraction unbound and glomerular filtration rate) for cefdinir was 5.94, a value indicating net renal tubular secretion. Anionic, cationic, and dipeptide transport inhibitors all significantly affected the cefdinir ER. With probenecid, the ER was reduced to 0.59, clearly demonstrating a significant reabsorptive component to cefdinir renal disposition. This finding was confirmed by glycylsarcosine studies, in which the ER was elevated to 7.95, indicating that reabsorption was mediated, at least in part, by the dipeptide transporter system. The effects of the organic cation tetraethylammonium, in which the ER was elevated to 7.53, were likely secondary in nature. The anionic secretory pathway was found to be the predominant mechanism for cefdinir renal excretion [2].

Protein binding. Perfusate samples collected during the actual IPK experiments (cefdinir with and without inhibitors) were subjected to ultrafiltration. Protein-free ultrafiltrate was obtained from perfusate using a disposable micropartition device and centrifugation. The device employs an anisotropic hydrophilic YMT membrane that excludes molecules larger than ∼30 kDa. Briefly, a 475-μl aliquot of perfusate was added to the device, which was then capped, equilibrated at 37°C for 15 min in a 35°C fixed-angle rotor, and then centrifuged for 25 min at 37°C and 1,800 × g. When necessary, the perfusate pH was adjusted prior to ultrafiltration to the original value obtained and recorded at the time of sample collection. Adjustment of the pH was made by gassing the sample with CO2 or by removing CO2 by vortexing the sample. Preliminary studies (data not shown) demonstrated that cefdinir was not appreciably bound to the ultrafiltration device and that protein leakage during the ultrafiltration process did not occur. Therefore, the fraction unbound of cefdinir (FU) in perfusate was calculated as the ratio of the cefdinir concentration in the ultrafiltrate to that in the perfusate [2].

Immediately following harvest of a kidney and prior to its transfer to the IPK apparatus, the kidney was carefully trimmed of adhering tissue and rinsed with warm (∼37°C) 10% normal saline to remove abdominal fluids. Care was taken during cleaning not to damage the capsular surface of the kidney. During this time, ∼20 ml of perfusate was allowed to pass through the kidney to remove any residual blood in the organ. The kidney was then transferred to the IPK apparatus, and recirculation was started. The perfusion apparatus was completely enclosed within a Plexiglas chamber maintained at 37°C by thermostatic control. During the experimental period, perfusion pressure at the tip of the renal cannula was kept at 80 ± 10 mm Hg (corrected for the intrinsic apparatus pressure) by way of the pressure and flow restriction valve. Initial perfusion pressure during the equilibration period was slightly higher but fell as hemodynamic equilibration was achieved. Following initiation of perfusion and harvest of the kidney, the organ was placed in the IPK apparatus and a 15-min period for homeostatic equilibration was allowed to pass. The experimental period began (t = 0) with the addition of 150 μl of [14C]inulin to the recirculating perfusion medium (16.7 μCi/ml; specific activity, 2.5 μCi/mg). In all IPK studies, cefdinir (5 μM) and potential transport inhibitors were dissolved separately in a small volume of perfusate and added to the recirculating medium immediately following the addition of [14C]inulin. A 15-min postdose equilibration period was then allowed for drug distribution and hemodynamic stability to occur. Following this period, the remaining 90 min of the experiment was divided into 10-min urine collection intervals for the evaluation of physiologic and clearance parameters. Urine was collected into, and its volume was measured with, a 1-ml tuberculin syringe. Perfusate (1.5 ml) was withdrawn from the sampling port with a 3-ml syringe (21-gauge needle) at the midpoint of each clearance interval (every 10 min). The perfusate and urine pHs were determined immediately after collection. During the experimental period, changes in perfusate composition due to the collection of urine and perfusate samples were minimized by isovolumetric replacement with modified Krebs-Henseleit buffer and blank perfusion medium (no inulin or other compounds present), respectively. Data from the postdose equilibration period (t = 0 to 15 min) were not included in the mean calculations or statistical evaluations. The parameters evaluated as descriptors of overall renal function included the urine flow rate, urine pH, perfusate flow rate, perfusate pH, perfusion pressure, renal vascular resistance (RVR), glomerular filtration rate (GFR), filtration fraction, and fractional excretion of glucose (FE glucose) and sodium (FE Na+). Cefdinir studies were performed in the absence of inhibitors to characterize the CLR of cefdinir alone in the IPK. Cefdinir inhibition studies were conducted in the presence of known competitive inhibitors of the renal organic anion (probenecid; PRO), organic cation (tetraethylammonium; TEA), and dipeptide (glycylsarcosine [Gly-Sar]) transport systems. Samples of the perfusate and urine were analyzed for concentrations of cefdinir, inulin, glucose, and sodium, as described below [2].

[1]. J Immunol.1994 Mar 1;152(5):2447-55.

[2]. Antimicrob Agents Chemother.2003 Feb;47(2):689-96.

[3]. J Immunol. 1994 Mar 1;152(5):2447-55.

C14H13N5O5S2

395.41

395.04

C, 42.53; H, 3.31; N, 17.71; O, 20.23; S, 16.22

91832-40-5

91832-40-5;213978-34-8 (salt);

Light yellow to yellow solid powder

-0.63

211.750

C=CC1=C(N2[C@@H]([C@@H](C2=O)NC(=O)/C(=N\O)/C3=CSC(=N3)N)SC1)C(=O)O

RTXOFQZKPXMALH-GHXIOONMSA-N

InChI=1S/C14H13N5O5S2/c1-2-5-3-25-12-8(11(21)19(12)9(5)13(22)23)17-10(20)7(18-24)6-4-26-14(15)16-6/h2,4,8,12,24H,1,3H2,(H2,15,16)(H,17,20)(H,22,23)/b18-7-/t8-,12-/m1/s1

(6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-hydroxyiminoacetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

PD 134393; PD-134393; PD134393; Cefdinir; Omnicef; CFDN; Cefdinirum; Cefdinyl; CI 983; CI-983; FK 482; FK-482; Omnicef.

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)

DMSO : 33.33~79 mg/mL (84.29~199.79 mM )

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.32 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.32 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (6.32 mM)

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