| Size | Price | |
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| 1mg | ||
| 5mg | ||
| 10mg | ||
| Other Sizes |
| Targets |
No specific pharmacological target reported. Functions as a substrate for drug transporters: multidrug resistance-associated protein 2 (Mrp2/ABCC2) for canalicular (biliary) efflux, and multidrug resistance-associated protein 3 (Mrp3/ABCC3) for basolateral (sinusoidal) efflux into blood [1].
Substrate for UDP-glucuronosyltransferases (UGTs), specifically UGT1A1, UGT1A6, UGT1A9, and UGT2B15, as the product of their enzymatic activity on acetaminophen [2]. |
|---|---|
| ln Vivo |
In Vivo: In male Wistar rats pretreated with a single dose (1.0 g/kg i.p.) or repeated increasing doses (0.2, 0.3, 0.6, 1.0 g/kg/day i.p.) of acetaminophen, the biliary excretion of a test dose of APAP-glu (150 mg/kg i.v. APAP) was significantly decreased by 70% and 80%, respectively, compared to vehicle controls. Conversely, urinary excretion of APAP-glu was significantly increased by 90% and 100%, respectively [1].
In rats pretreated with repeated doses of APAP, the enterohepatic recirculation of APAP-glu was significantly decreased. This was evidenced by a 70% reduction in biliary excretion of the glucuronide under conditions of preserved enterohepatic circulation, while no difference was observed under permanent biliary drainage [1]. |
| Enzyme Assay |
Enzyme Assay: For the assessment of UDP-glucuronosyltransferase (UGT) activity toward acetaminophen, liver microsomes were prepared. Incubation conditions incorporated Triton X-100 to activate microsomes. After incubation, the reaction mixture was deproteinized, and the formed APAP-glu in the supernatant was detected and quantified by HPLC. This method was used to confirm that UGT activity toward APAP was not significantly modified by APAP pretreatment protocols [1].
An in vitro vesicular transport assay was used to measure ATP-dependent uptake of the Mrp3 substrate taurocholate into basolateral liver plasma membrane (BLPM) vesicles. BLPM vesicles (80 µg protein) were mixed with transport medium containing 1.5 µM radiolabeled taurocholate, 5 mM ATP, and an ATP-regenerating system (10 mM creatine phosphate and 100 µg/mL creatine phosphokinase) or 5 mM AMP. The reaction was stopped at 20, 40, 60, and 120 seconds by adding ice-cold buffer, and the mixture was filtered through a 0.45 µm membrane filter. Radioactivity retained on the filter was determined. This assay showed that ATP-dependent taurocholate transport was significantly increased in BLPM from rats pretreated with repeated doses of APAP, consistent with increased Mrp3 expression [1]. |
| Animal Protocol |
Animal Protocol: For the biliary and urinary excretion study, male Wistar rats were pretreated with APAP (single 1.0 g/kg i.p. or repeated increasing doses of 0.2, 0.3, 0.6, 1.0 g/kg/day i.p.). Twenty-four hours after the last dose, rats were anesthetized with sodium pentobarbital (50 mg/kg i.p.). The jugular vein, common bile duct, and urinary bladder were cannulated. A test dose of APAP (150 mg/kg i.v.) was administered. Bile was collected at 15-min intervals and urine at 30-min intervals for 3 hours to measure APAP-glu content by HPLC [1].
For the enterohepatic recirculation study, rats pretreated with the repeated APAP protocol were anesthetized, and the jugular vein was cannulated. A test dose of APAP (150 mg/kg i.v.) was administered. After 150 minutes, the common bile duct was cannulated, and bile was collected for 30 minutes to measure APAP-glu content by HPLC. This was compared to the 150-180 min period from animals under permanent biliary drainage [1]. |
| ADME/Pharmacokinetics |
ADME/Pharmacokinetics: In humans at therapeutic doses, APAP-glu is the major urinary metabolite, accounting for 52-57% of excreted urinary metabolites [2].
At supratherapeutic doses (>4 g/day), the glucuronidation pathway becomes saturated, leading to a smaller proportion of the dose being eliminated as APAP-glu. In fatal centrilobular hepatic necrosis, plasma and urinary levels of the glucuronide metabolite are barely detectable [2]. The disposition of APAP-glu involves complex inter-organ transport. From the liver, most of the glucuronide is transported into the kidneys through the bloodstream, while some appears in the bile with subsequent transport through the intestines back into the blood. The plasma half-life of APAP (parent drug) is 1.5-2.5 hours at therapeutic doses, which is prolonged to 4-8 hours after an overdose [2]. In rats, the cumulative biliary excretion of APAP-glu after a test dose of APAP was decreased by 70-80% in APAP-pretreated groups, while cumulative urinary excretion was increased by 90-100% [1]. |
| Toxicity/Toxicokinetics |
Toxicity/Toxicokinetics: APAP-glu itself is considered a non-toxic, pharmacologically inactive metabolite. Its altered disposition (shift from biliary to urinary excretion) due to Mrp3 induction is postulated to contribute to decreased hepatotoxicity by reducing enterohepatic recirculation and thus liver exposure to the parent drug, APAP [1].
No direct toxicity data for APAP-glu were reported. |
| References |
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| Additional Infomation |
APAP-glu is formed via the glucuronidation of acetaminophen (APAP), a reaction catalyzed by UDP-glucuronosyltransferase (UGT) enzymes, primarily UGT1A6 at low APAP concentrations, and UGT1A9 and UGT1A1 at toxic doses. UGT2B15 is also involved [2].
In rats, the shift from biliary to urinary excretion of APAP-glu following APAP pretreatment correlated with a marked increase (over 400%) in hepatic expression of the basolateral transporter Mrp3, relative to a 65% increase in the canalicular transporter Mrp2. This selective induction leads to preferential basolateral efflux into blood, followed by urinary elimination, rather than biliary excretion. This change in disposition was also associated with decreased enterohepatic recirculation of the drug [1]. In humans, a genetic polymorphism in UGT1A (rs8330) is associated with increased liver acetaminophen glucuronidation and a decreased risk of unintentional acetaminophen-induced acute liver failure. The UGT2B152 polymorphism significantly influences APAP glucuronidation, with the percentage of APAP-glu diminished across genotypes from 1/1 to 2/2 [2]. |
| Molecular Formula |
C14H16NNAO8
|
|---|---|
| Molecular Weight |
349.26854
|
| Exact Mass |
349.077
|
| Elemental Analysis |
C, 48.14; H, 4.62; N, 4.01; Na, 6.58; O, 36.65
|
| CAS # |
120595-80-4
|
| Related CAS # |
16110-10-4 (free acid); 120595-80-4 (sodium)
|
| PubChem CID |
23677080
|
| Appearance |
White to off-white solid powder
|
| Melting Point |
232-233ºC (dec)
|
| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
24
|
| Complexity |
443
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CC(=NC1=CC=C(C=C1)O[C@H]2[C@@H]([C@H]([C@@H]([C@@H](C(=O)O)O2)O)O)O)[O-].[Na+]
|
| InChi Key |
OINXIJJEOMGKPB-UHFFFAOYSA-M
|
| InChi Code |
InChI=1S/C14H17NO8.Na/c1-6(16)15-7-2-4-8(5-3-7)22-14-11(19)9(17)10(18)12(23-14)13(20)21;/h2-5,9-12,14,17-19H,1H3,(H,15,16)(H,20,21);/q;+1/p-1
|
| Chemical Name |
sodium;6-(4-acetamidophenoxy)-3,4,5-trihydroxyoxane-2-carboxylate
|
| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
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
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| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8631 mL | 14.3156 mL | 28.6311 mL | |
| 5 mM | 0.5726 mL | 2.8631 mL | 5.7262 mL | |
| 10 mM | 0.2863 mL | 1.4316 mL | 2.8631 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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