| Targets |
Brdu; PI3K/Akt; Endogenous Metabolite; Microbial Metabolite
|
|---|---|
| ln Vitro |
The progressive, often fatal myopathy seen in Thymidine Kinase 2 deficiency (TK2d) is caused by mutations in the nuclear TK2 gene, leading to a dysfunctional or deficient mitochondrial TK2 enzyme. This enzyme is essential for phosphorylating the pyrimidine nucleosides doxecitine (dC) and thymidine (dT) into dCMP and dTMP, which are precursors for the deoxyribonucleotide triphosphates (dNTPs) required for mitochondrial DNA (mtDNA) maintenance and replication. The resulting metabolic block causes severe mtDNA depletion and dysfunction of the mitochondrial respiratory chain.[] Doxecitine, in combination with doxribtimine, functions as a nucleoside substrate enhancement therapy that successfully bypasses the defective mitochondrial pathway. The high concentrations of exogenous dC and dT are primarily phosphorylated by intact cytosolic salvage enzymes, specifically Deoxycytidine Kinase (dCK) and Thymidine Kinase 1 (TK1). The nucleosides are actively transported into cells and across the blood-brain barrier via equilibrative nucleoside transporters. The resulting phosphorylated dNTP precursors are then made available to the mitochondria. This replenishes the critically depleted dNTP pools, which facilitates the replication of mtDNA by the mitochondrial DNA Polymerase gamma.
|
| ln Vivo |
Doxecitine's primary action is a substrate enhancement therapy that corrects the nucleoside imbalance caused by TK2d deficiency. The goal is to provide a high systemic concentration of deoxycytidine and deoxythymidine that can be utilized by unaffected salvage pathways. This action restores the synthesis of mitochondrial DNA (mtDNA) precursors, leading to the restoration of mtDNA copy number and subsequent improvement in respiratory chain enzyme (RCE) activities in affected tissues. This systemic correction counteracts the relentless muscle weakness and respiratory failure characteristic of TK2d, resulting in the amelioration of myopathy, delay of disease onset, and significantly prolonged survival in both preclinical models and patients.
|
| ADME/Pharmacokinetics |
Absorption
Doxepin is rapidly absorbed after oral administration, with plasma concentrations returning to near baseline levels within 8 to 12 hours. The absolute bioavailability of orally administered doxepin has not been determined. The median time to peak plasma concentration (Tmax) for doxepin is approximately 2 hours. Elimination Pathway In healthy subjects, less than 1% of the dose of intact doxepin and doxepin is excreted in urine after oral administration of doxepin and doxepinibamine. Protein Binding In vitro plasma protein binding is less than 10% in the concentration range of 0.23 mcg/mL to 23 mcg/mL. Metabolism/Metabolites Doxepin is primarily degraded by cytidine deaminase to the nucleotide and 2-deoxy-α-D-ribose-1-phosphate moiety. The intermediate products of doxexetine's catabolism are deoxyuridine, uracil, and dihydrouracil, while the final products are β-alanine, ammonia, and carbon dioxide (CO2). Biological Half-Life In healthy adult subjects, after a single oral dose of 133 mg/kg doxexetine while in a food-containing state, the average half-life is approximately 1 hour. |
| Toxicity/Toxicokinetics |
About KYGEVVI
KYGEVVI is a combination of doxexicetin and docelibutemine, both pyrimidine nucleosides, indicated for the treatment of thymidine kinase 2 deficiency (TK2d) in adults and children 12 years and younger. KYGEVVI is administered to incorporate pyrimidine nucleosides (deoxycytidine and deoxythymidine) into skeletal muscle mitochondrial DNA.1This action restores mitochondrial DNA copy number in TK2d mutant mice. Important Safety Information for KYGEVVI1 Elevated Liver Transaminases Elevated levels of liver transaminases [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] have been reported in patients treated with KYGEVVI. Baseline liver transaminase (ALT, AST) and total bilirubin levels should be obtained before initiating KYGEVVI treatment. If signs or symptoms consistent with liver injury are observed, KYGEVVI treatment should be discontinued until liver transaminase (ALT, AST) and total bilirubin levels return to baseline or stabilize at a new baseline value. If signs or symptoms consistent with liver injury persist or worsen, permanent discontinuation of KYGEVVI should be considered. Liver transaminase and total bilirubin levels should be monitored annually and as clinically necessary. Gastrointestinal Adverse Reactions Patients receiving KYGEVVI treatment have reported diarrhea and vomiting, leading to hospitalization, dose reduction, and permanent discontinuation. Depending on the severity of diarrhea and/or vomiting, the dose of KYGEVVI should be reduced or treatment should be discontinued until diarrhea and/or vomiting improve or return to baseline levels. Consider restarting KYGEVVI from the previously tolerated dose and gradually increasing the dose based on tolerance. For persistent or recurrent diarrhea and/or vomiting, permanent discontinuation of KYGEVVI should be considered, along with supportive care such as electrolyte supplementation as clinically necessary. |
| References |
|
| Additional Infomation |
2'-Deoxycytidine is a pyrimidine 2'-deoxynucleoside with cytosine as its nucleobase. It functions as a metabolite in humans, Saccharomyces cerevisiae, Escherichia coli, and mice. Functionally, it is related to cytosine. Deoxycytidine is a metabolite found in or produced by Escherichia coli (K12 strain, MG1655 strain). It has been reported to be present in Homo sapiens, Hedgehogaea, and other organisms with relevant data. Doxycycline is a nucleoside component of DNA, composed of cytosine and deoxyribose, and possesses chemopreventive activity. 2'-Deoxycytidine is a metabolite found in or produced by Saccharomyces cerevisiae. It is a nucleoside component of DNA, composed of cytosine and deoxyribose.
|
| Molecular Formula |
C9H13N3O4
|
|---|---|
| Molecular Weight |
227.22
|
| Exact Mass |
227.09
|
| Elemental Analysis |
C, 47.57; H, 5.77; N, 18.49; O, 28.16
|
| CAS # |
951-77-9
|
| Related CAS # |
3992-42-5 (HCl);951-77-9;
|
| PubChem CID |
13711
|
| Appearance |
White to off-white solid powder
|
| Density |
1.7±0.1 g/cm3
|
| Boiling Point |
482.1±55.0 °C at 760 mmHg
|
| Melting Point |
209-211 °C(lit.)
|
| Flash Point |
245.4±31.5 °C
|
| Vapour Pressure |
0.0±2.7 mmHg at 25°C
|
| Index of Refraction |
1.720
|
| LogP |
-1.73
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
2
|
| Heavy Atom Count |
16
|
| Complexity |
355
|
| Defined Atom Stereocenter Count |
3
|
| SMILES |
C1[C@@H]([C@H](O[C@H]1N2C=CC(=NC2=O)N)CO)O
|
| InChi Key |
CKTSBUTUHBMZGZ-SHYZEUOFSA-N
|
| InChi Code |
InChI=1S/C9H13N3O4/c10-7-1-2-12(9(15)11-7)8-3-5(14)6(4-13)16-8/h1-2,5-6,8,13-14H,3-4H2,(H2,10,11,15)/t5-,6+,8+/m0/s1
|
| Chemical Name |
4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one
|
| Synonyms |
Cytosine; Doxecitine; Deoxycytidine; SR-13668; Desoxycytidin; Cytosine deoxyriboside; SR13668; Deoxyribose cytidine; SR 13668; deoxyriboside; 2'-deoxycytidine; 951-77-9; deoxycytidine; CYTIDINE, 2'-DEOXY-; dCYD; Desoxycytidin
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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) |
DMSO : ~50 mg/mL (~220.05 mM)
H2O : ~50 mg/mL (~220.05 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (11.00 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (11.00 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (11.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 110 mg/mL (484.11 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.4010 mL | 22.0051 mL | 44.0102 mL | |
| 5 mM | 0.8802 mL | 4.4010 mL | 8.8020 mL | |
| 10 mM | 0.4401 mL | 2.2005 mL | 4.4010 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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