Tebipenem Pivoxil has high intestinal apical membrane permeability due to plural intestinal transport routes, including the uptake transporters such as OATP1A2 and OATP2B1 as well as simple diffusion. Tebipenem Pivoxil is quickly converted to tebipenem (TBPM), an active form of Tebipenem Pivoxil. Tebipenem Pivoxil are absorbed quickly, and the bioavailability is 71.4%, 59.1%, 34.8% and 44.9%, respectively, in mouse, rat, dog and monkey. Tebipenem shows the strongest bactericidal activity as early as 2 h after exposure at two times the MIC. Tebipenem shows higher affinities for PBP 1A and PBP 2B, high-molecular-weight enzymes, and for PBP 3, a low-molecular-weight enzyme, than for PBP 2X. Tebipenem has a potent activity against Neisseria gonorrhoeae; its activity is comparable to it of cefixime that has most potent activity among oral antibiotics.

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Tebipenem Pivoxil uptake by Caco-2 cells was decreased by ATP-depletion (to 53% of control) and by lowering temperature to 4°C (to 73% of control), suggesting carrier-mediated transport. [1]
Uptake was dose-dependently inhibited by captopril and ascorbic acid, and weakly inhibited by cholic acid and valproic acid; cationic compounds (tetraethylammonium, L-carnitine) had no effect. [1]
Among ACE inhibitors, enalapril showed potent inhibition, lisinopril weak inhibition, while cephalexin and sulpiride (PEPT substrates) and quercetin (SVCT inhibitor) had no effect. [1]
Captopril and ascorbic acid inhibited Tebipenem Pivoxil uptake but not cefditoren pivoxil uptake in Caco-2 cells. [1]
In Xenopus oocytes expressing human OATP1A2 and OATP2B1, significant uptake of Tebipenem Pivoxil was observed (vs water-injected oocytes), while no uptake was observed by PEPT1-expressing oocytes. [1]
Tebipenem Pivoxil inhibited OATP1A2- and OATP2B1-mediated uptake of estrone-3-sulfate (10 nM) in a dose-dependent manner with IC50 values of 8.0 μM (OATP1A2) and 410 μM (OATP2B1) at pH 6.0. [1]
Kinetic analysis showed saturable transport by OATP1A2 with a Km of 41.1 μM; OATP2B1-mediated uptake was not saturated up to 1 mM (Km >1 mM). [1]
pH dependence: OATP1A2-mediated uptake was highest at pH 6.5 (bell-shaped), while OATP2B1-mediated uptake increased with increasing pH (higher at neutral/weak alkaline). [1]

Tebipenem Pivoxil results in survival rate of 83%, compared with 25% survival for Amoxicillin and 0% survival for controls in animal model of otitis media. Tebipenem exhibits slow tight-binding inhibition at low micromolar concentrations versus the chromogenic substrate nitrocefin. Tebipenem acyl-enzyme complex remains stable for greater than 90 min and exists as mixture of the covalently bound drug and the bound retro-aldol cleavage product.
In rats, oral co-administration of captopril (300 mg/kg) with Tebipenem Pivoxil (5 mg/kg) significantly reduced plasma TBPM (active form) concentrations: Cmax decreased from 2.88±0.35 to 1.01±0.34 μg/mL, and AUC0-inf from 1.52±0.12 to 0.50±0.07 μg·h/mL (p<0.05). No significant effect was observed on cefditoren pivoxil absorption. [1]
In rat in situ intestinal single-pass perfusion study (ileum segment, 100 μM Tebipenem Pivoxil with or without 10 mM captopril), captopril significantly reduced TBPM concentration in mesenteric venous blood, with AUC0-obs reduced from 4372±333 to 2363±606 ng·min/mL and absorption rate reduced from 0.10±0.00 to 0.05±0.02 nmol/min (p<0.05). [1]

Caco-2 cell uptake study: Cells were seeded in 24-well plates (1×10^5 cells/well) and cultured for 18-24 h. After washing with PBS, cells were incubated with 100 μM Tebipenem Pivoxil or [14C]-labeled compound in uptake buffer (HBSS with 110 mM HEPES, pH 7.2) at 37°C for 15 min. For ATP depletion, cells were pretreated with 1 mM 2,4-dinitrophenol for 15 min. For low temperature, incubation at 4°C. After washing with ice-cold PBS, cells were lysed in MOPS buffer (pH 6.0)/acetonitrile/methanol (50:45:5). Supernatant was analyzed by LC/MS (monitoring m/z 498 for TBPM-PI, m/z 384 for TBPM). [1]
Xenopus oocyte uptake study: Oocytes were microinjected with cRNA of OATP1A2, OATP2B1, or water (control), and cultured for 3 days. For PEPT1, commercial oocytes were used. Uptake of Tebipenem Pivoxil (10-1000 μM) was measured in modified Barth's solution (pH 5.0-8.0) at room temperature for 60 min. After washing, oocytes were lysed and analyzed by LC/MS. Transporter expression was confirmed with estrone-3-sulfate (for OATPs) or glycylsarcosine (for PEPT1). [1]

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Rat in vivo study: Male SD rats (8-9 weeks) fasted >15 h were cannulated in the femoral artery under diethyl ether anesthesia. Tebipenem Pivoxil dosing solution (2 mg/mL in 5% HCO-60, pH 6.5) was administered orally at 5 mg/kg with or without captopril (300 mg/kg). Blood was collected from femoral artery at 5,15,30,45,60,90,120 min. Plasma TBPM concentration was measured by LC/MS. Pharmacokinetic parameters calculated by noncompartmental analysis using WinNonlin. [1]
Rat in situ single-pass intestinal perfusion study: Male SD rats (8-9 weeks) fasted >15 h were anesthetized with pentobarbital. A 5 cm ileal segment was cannulated and perfused with DPBS (pH 6.5) containing 100 μM Tebipenem Pivoxil with or without 10 mM captopril at 0.2 mL/min. Venous blood from mesenteric vein was collected at 4-min intervals for 28 min. Plasma TBPM concentration measured by LC/MS. Absorption rate (V) calculated as Q × Clast, where Q is blood flow rate and Clast is concentration at 28 min. [1]

Human oral absorption (cumulative urinary excretion of active form TBPM) of Tebipenem Pivoxil is 54-73%, which is higher than other prodrug-type β-lactam antibiotics (cefditoren pivoxil 20%, cefcapene pivoxil 33-41%, cefetamet pivoxil 41-51%, cefuroxime axetil 32-45%, cefpodoxime proxetil 36-45%, cefteram pivoxil 27%). [1]
In rats, after oral administration of Tebipenem Pivoxil (5 mg/kg), pharmacokinetic parameters were: t1/2 = 0.15±0.02 h, tmax = 0.25±0.00 h, Cmax = 2.88±0.35 μg/mL, AUC0-inf = 1.52±0.12 μg·h/mL. Co-administration with captopril (300 mg/kg) significantly reduced these values (Cmax 1.01±0.34 μg/mL, AUC0-inf 0.50±0.07 μg·h/mL). [1]
The active form TBPM is not transported by OATP1A2 or OATP2B1; only the prodrug is a substrate. [1]
The absorption mechanism involves both simple diffusion and carrier-mediated transport via OATP1A2 and OATP2B1, with possible saturation of OATP1A2 at clinical doses due to its Km of 41.1 μM. [1]

Mol Pharm.2010 Oct 4;7(5):1747-56;Jpn J Antibiot.2009 Jun;62(3):214-40;Vaccine.2007 Mar 22;25(13):2478-84.

Tibipenem pivoxil belongs to the carbapenem class of antibiotics and is a neopentanoyloxymethyl ester. Tibipenem pivoxil is an orally effective prodrug of telbipenem, a broad-spectrum 1β-methylcarbapenem antibiotic with a 1-(1,3-thiazolin-2-yl)azacyclobutane-3-yl thio group attached at the C-2 position. Upon oral administration of telbipenem pivoxil, the ester bond cleaves, releasing the active drug telbipenem. See also: Telbipenem (note moved to).

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Tebipenem Pivoxil is a prodrug that is hydrolyzed by carboxylesterase in intestinal epithelial cells to release the active antibiotic tebipenem (TBPM). It is indicated for otolaryngologic and respiratory infections in pediatric patients. Its high oral absorption (54-73% in humans) reduces the risk of insufficient efficacy and emergence of resistant bacteria, as well as intestinal side effects like diarrhea and microbial substitution compared to antibiotics with low oral absorption. The compound has a pKa of 7.72 (for the thiazolinylazetidine group), existing mainly as a cation under weak acidic conditions in the small intestine. [1]

C22H31N3O6S2

497.63

497.165

C, 53.10; H, 6.28; N, 8.44; O, 19.29; S, 12.89

161715-24-8

Tebipenem;161715-21-5;Tebipenem pivoxil hydrochloride;211558-19-9

9892071

White to off-white solid powder

1.5±0.1 g/cm3

661.9±65.0 °C at 760 mmHg

140-142℃

354.1±34.3 °C

0.0±4.5 mmHg at 25°C

1.688

-0.45

1

9

10

33

908

4

S(C1([H])C([H])([H])N(C2=NC([H])([H])C([H])([H])S2)C1([H])[H])C1=C(C(=O)OC([H])([H])OC(C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])=O)N2C([C@]([H])([C@@]([H])(C([H])([H])[H])O[H])[C@@]2([H])[C@@]1([H])C([H])([H])[H])=O

SNUDIPVBUUXCDG-GBOPCIDUSA-N

InChI=1S/C22H31N3O6S2/c1-11-15-14(12(2)26)18(27)25(15)16(19(28)30-10-31-20(29)22(3,4)5)17(11)33-13-8-24(9-13)21-23-6-7-32-21/h11-15,26H,6-10H2,1-5H3/t11-,12-,14-,15+/m1/s1

(pivaloyloxy)methyl (4R,5R,6S)-3-((1-(4,5-dihydrothiazol-2-yl)azetidin-3-yl)thio)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

ME1211; ME-1211; ME 1211; SPR994; SPR-994; SPR 994; TBM-PI; Tebipenem pivoxil

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 : 99~200 mg/mL ( 198.94~401.91 mM )
Ethanol : ~87 mg/mL

Solubility in Formulation 1: ≥ 5 mg/mL (10.05 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 50.0 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: ≥ 5 mg/mL (10.05 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 50.0 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: ≥ 5 mg/mL (10.05 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 50.0 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: ≥ 5 mg/mL (10.05 mM)

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