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| 10mg | ||
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Valacyclovir HCl hydrate is a potent antiviral agent with activity against herpes simplex, herpes zoster and herpes B. It is a prodrug that needs to be converted into acyclovir in vivo.
| Targets |
HSV-1 (IC50 = 2.9 μg/mL)
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| ln Vitro |
At concentrations of 1.64 mM and 23.34 nmol/mg protein/5 min, respectively, the maximal rates of valacyclovir hydrochloride (valaciclovir hydrochloride, VACV) uptake are concentration-dependent and saturable. The in vitro intestinal transport properties of VACV are dominated by hPEPT1, as demonstrated by the very identical Km values observed in hPEPT1/CHO cells, rat and rabbit tissues, and Caco-2 cells [3].
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| ln Vivo |
The objective of this study was to investigate the processability of hot-melt extrusion (HME) to formulate ocular inserts of valacyclovir hydrochloride and evaluate the in vivo bioavailability of the formulation. To optimize the formulation of this drug, different physical mixtures of the polymers and plasticizer were prepared. The physical mixture was extruded through a co-rotating twin-screw extruder, and the obtained ocular inserts were cut with dimensions of 4 mm × 2 mm × 1 mm to enhance the formulation instillation in the eye. Ocular inserts were evaluated for drug content, weight variation, uniformity of thickness, in vitro drug release, and in vivo drug bioavailability. The ocular inserts were thermally characterized using differential scanning calorimetry (DSC). The attributes observed for the ocular inserts were within the target specifications. The ocular inserts of valacyclovir hydrochloride were successfully prepared using the HME. They provided sustained drug release along with enhanced drug permeation when compared with the eyedrop solution and dissolve completely in 8 h. Additionally, the obtained results demonstrated that the formulation of ocular inserts of valacyclovir hydrochloride using HME was reproducible, robust, and effective method[2].
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| Cell Assay |
The results of previous work performed in our laboratory using an in situ perfusion technique in rats and rabbit apical brush border membrane vesicles have suggested that the intestinal uptake of valacyclovir (VACV) appears to be mediated by multiple membrane transporters. Using these techniques, it is difficult to characterize the transport kinetics of VACV with each individual transporter in the presence of multiple known or unknown transporters. The purpose of this study was to characterize the interaction of VACV and the human intestinal peptide transporter using Chinese hamster ovary (CHO) cells that overexpress the human intestinal peptide transporter (hPEPT1) gene. VACV uptake was significantly greater in CHO cells transfected with hPEPT1 than in cells transfected with only the vector, pcDNA3. The optimum pH for VACV uptake was determined to occur at pH 7.5. Proton cotransport was not observed in hPEPT1/CHO cells, consistent with previously observed results in tissues and Caco-2 cells. VACV uptake was concentration dependent and saturable with a Michaelis-Menten constant and maximum velocity of 1.64 +/- 0.06 mM and 23.34 +/- 0.36 nmol/mg protein/5 min, respectively. A very similar Km value was obtained in hPEPT1/CHO cells and in rat and rabbit tissues and Caco-2 cells, suggesting that hPEPT1 dominates the intestinal transport properties of VACV in vitro. VACV uptake was markedly inhibited by various dipeptides and beta-lactam antibiotics, and Ki values of 12.8 +/- 2.7 and 9.1 +/- 1.2 mM were obtained for Gly-Sar and cefadroxil at pH 7.5, respectively. The present results demonstrate that VACV is a substrate for the human intestinal peptide transporter in hPEPT1/CHO cells and that although transport is pH dependent, proton cotransport is not apparent. Also, the results demonstrate that the hPEPT1/CHO cell system has use in investigating the transport kinetics of drugs with the human intestinal peptide transporter hPEPT1; however, the extrapolation of these transport properties to the in vivo situation requires further investigation[3].
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| Animal Protocol |
Acyclovir has been a frequently used antiviral agent in the clinical treatment of leukemia, acute encephalitis, malignant tumor and herpes simplex. The adverse effects of this drug have been widely described in clinical practice. In the present study, a case of a 35-year-old female patient diagnosed with herpes simplex, who developed acute renal injury following treatment with valacyclovir hydrochloride, is described. Kidney biopsy, light microscopy and laboratory examination were performed, and all findings revealed the signs of evident vacuolar degeneration of capillary endothelial and renal tubular epithelial cells, erythrocyte aggregation in partial renal tubule and microvilli exfoliation from epithelial cells. Renal interstitial edema was clearly identified. The clinical evidence observed from this female patient indicated that renal functions should be closely monitored during valacyclovir hydrochloride administration. A variety of effective measures, such as hydration, alkalizing urine, promoting the discharge of medication and the use of antagonists are recommended following the administration of antiviral agents[1].
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| References |
[3]. Guo A, Hu P, Balimane PV, Interactions of a nonpeptidic drug, valacyclovir, with the human intestinal peptide transporter (hPEPT1) expressed in a mammalian cell line.J Pharmacol Exp Ther. 1999 Apr;289(1):448-54.
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| Molecular Formula |
C13H23CLN6O5
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|---|---|
| Molecular Weight |
378.81
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| Exact Mass |
378.141845
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| CAS # |
1218948-84-5
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| Related CAS # |
Valacyclovir hydrochloride;124832-27-5;Valacyclovir;124832-26-4
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| PubChem CID |
171360722
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| Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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| tPSA |
144Ų
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| SMILES |
C(N1C=NC2C(N=C(N)NC1=2)=O)OCCOC(=O)[C@@H](N)C(C)C.Cl.O
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| InChi Key |
FMHJVOWOKISDAI-NWWUXDCXSA-N
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| InChi Code |
InChI=1S/C13H20N6O4.ClH.H2O/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20;;/h5,7-9H,3-4,6,14H2,1-2H3,(H2,15,18,20);1H;1H2/t8-,9?;;/m0../s1
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| Chemical Name |
2-[(2-imino-6-oxo-5H-purin-9-yl)methoxy]ethyl (2S)-2-amino-3-methylbutanoate;hydrate;hydrochloride
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| 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)
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| 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 | 2.6398 mL | 13.1992 mL | 26.3985 mL | |
| 5 mM | 0.5280 mL | 2.6398 mL | 5.2797 mL | |
| 10 mM | 0.2640 mL | 1.3199 mL | 2.6398 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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