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Valacyclovir (Zelitrex; BW256; Val-ACV; Valtrex; BW-256U87) is a potent antiviral drug used in the management of herpes simplex, herpes zoster, and herpes B. Valacyclovir is a prodrug that has to be converted in vivo to aciclovir. As an esterified prodrug of aciclovir, Valacyclovir has greater oral bioavailability (about 55%) than aciclovir (10–20%). It is converted by esterases to the active drug aciclovir, as well as the amino acid valine, via hepatic first-pass metabolism. Aciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase.
| Targets |
HSV-1 (IC50 = 2.9 μg/mL)
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| ln Vitro |
Valaciclovir (VACV) has maximal rates of 23.34 nmol/mg protein/5 minutes and 1.64 mM, respectively, according to Michaelis-Menten constants, with concentration-dependent and saturable absorption. The Km values in rat, rabbit, and Caco-2 cells, as well as in hPEPT1/CHO cells, were quite similar, suggesting that hPEPT1 controls the in vitro intestinal transport characteristics of VACV [5].
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| ln Vivo |
A major comparative trial found that valacyclovir (1 g twice day) for 10 days was just as effective as acyclovir (200 mg 5 times daily) for treating a first bout of genital herpes. Two trials found that valacyclovir (200 mg five times daily) was equally efficacious as acyclovir (200 mg five times daily) in a five-day treatment cycle for managing relapses. Valacyclovir at a dose of 1 g per day works just as well as 2 g per day. One dose of valacyclovir can be given every day [1]. Serum and cerebrospinal fluid acyclovir concentrations were assessed at steady state following six days of oral valacyclovir 1,000 mg three times a day [2]. PE and AC have EC50 values in 3T3 cells of 0.02 and 0.01 ug/ml, however in BHK cells they are 0.2 and 0.03 ug/ml. Immunosuppressed mice that were infected were treated with FA and VA (bid, 5.5 days) to eradicate otoparesis, ear lesions (vesicles, etc.), and death. The percentage of erythema was also reduced from 100% to 24% and 38%. By day six, the virus had vanished from the ears and brainstem, but in mice receiving VA treatment, it returned when the medication was stopped [3].
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| Enzyme Assay |
The in vitro 50% inhibitory concentration (IC50) of HSV-1 W strain was determined by using a plaque-reduction assay to verify its sensitivity to acyclovir. The IC50 for HSV-1 W was determined to be 2.9 µg/ml. [4].
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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[5].
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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 |
[1]. Valacyclovir. New indication: for genital herpes, simpler administration. Can Fam Physician. 1999 Jul;45:1698-700, 1703-5.
[2]. Lycke J, et al. Acyclovir levels in serum and cerebrospinal fluid after oral administration of valacyclovir. Antimicrob Agents Chemother. 2003 Aug;47(8):2438-41. [3]. Comparison of efficacies of famciclovir and valaciclovir against herpes simplex virus type 1 in a murineimmunosuppression model. Antimicrob Agents Chemother. 1995 May;39(5):1114-9. [4]. Dhaliwal DK, Romanowski EG, Yates KA, Valacyclovir inhibits recovery of ocular HSV-1 after experimental reactivation by excimer laser keratectomy. Cornea. 1999 Nov;18(6):693-9. [5]. 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. |
| Additional Infomation |
Valacyclovir is a L-valyl ester. It has a role as an antiviral drug. It is functionally related to a guanine.
Valaciclovir (valacyclovir), also known as Valtrex, is an antiviral drug that has been used to manage and treat various herpes infections for more than 2 decades. It was initially approved by the FDA in 1995 and marketed by GlaxoSmithKline. Valacyclovir is the L-valine ester of aciclovir. It is a member of the purine (guanine) nucleoside analog drug class. This class of drugs forms an important part of hepatitis, HIV, and cytomegalovirus drug regimens. One major use of valacyclovir is the treatment of genital herpes episodes or outbreaks. Genital herpes is a frequently diagnosed sexually transmitted disease which currently affects more than 400 million individuals worldwide. It is caused by infection with the herpes simplex virus (HSV). Infection with this virus is lifelong with periodic episodes of reactivation.
Valacyclovir is a Herpes Simplex Virus Nucleoside Analog DNA Polymerase Inhibitor, and Herpes Zoster Virus Nucleoside Analog DNA Polymerase Inhibitor, and Herpesvirus Nucleoside Analog DNA Polymerase Inhibitor. The mechanism of action of valacyclovir is as a DNA Polymerase Inhibitor. View MoreValacyclovir is a nucleoside analogue antiviral agent and prodrug of acyclovir which is used in therapy of herpes simplex and varicella-zoster virus infections. Valacyclovir has been associated with rare instances mild, clinically apparent liver injury. Valacyclovir is the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir. Orally administered, valacyclovir is rapidly converted to acyclovir which inhibits viral DNA replication after further conversion to the nucleotide analog acyclovir triphosphate by viral thymidine kinase, cellular guanyl cyclase, and a number of other cellular enzymes. Acyclovir triphosphate competitively inhibits viral DNA polymerase; incorporates into and terminates the growing viral DNA chain; and inactivates viral DNA polymerase. The greater antiviral activity of acyclovir against herpes simplex virus (HSV) compared with varicella-zoster virus (VZV) is due to its more efficient phosphorylation by HSV thymidine kinase. A prodrug of acyclovir that is used in the treatment of HERPES ZOSTER and HERPES SIMPLEX VIRUS INFECTION of the skin and mucous membranes, including GENITAL HERPES. Valacyclovir is a nucleoside analog DNA polymerase inhibitor indicated for: **Adults** • Cold Sores (Herpes Labialis) • Genital Herpes • Treatment of genital herpes lesions in immunocompetent patients (initial or recurrent episode) • Suppression of genital herpes lesions in immunocompetent or HIV-infected patients • Reduction of viral transmission • Herpes Zoster **Pediatric Patients** • Cold Sores (Herpes Labialis) • Chickenpox **Limitations of use** The efficacy and safety of valacyclovir have not been established in immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients. Valacyclovir is a nucleoside analogue antiviral agent and prodrug of acyclovir which is used in therapy of herpes simplex and varicella-zoster virus infections. Valacyclovir has been associated with rare instances mild, clinically apparent liver injury. Valacyclovir shows varying levels of inhibition towards herpes simplex virus types 1 (HSV-1), 2 (HSV-2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response of humans to the same antiviral therapy has not yet been elucidated. Sensitivity testing results, described by the concentration of drug needed to inhibit the growth of the virus by 50% in cell culture (EC50), vary widely depending on various factors. **Clinical study results** For the various conditions below, clinical study results are summarized as follows: _Cold sores_ Immunocompetent volunteers with cold sores were observed following the administration of a 1-day regimen (2 grams of valacyclovir twice a day for 1 day followed by one day of placebo) or a 2-day regimen (2 grams of valacyclovir twice daily for two days). The average duration of cold sore episodes was approximately 1 day shorter in treated subjects when compared to subjects treated with placebo. A 2-day drug administration regimen of valacyclovir did not provide superior benefit over the 1-day regimen. There was no clinically significant difference observed between subjects receiving valacyclovir or placebo in the prevention of progression of cold sore lesions after the papular stage, indicating that timing of valacyclovir administration is an important consideration. _Initial genital herpes episodes_ 643 immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). In both groups, the median time to healing of herpetic lesions was measured to be 9 days, and the median time to cessation of pain was found to be 5 days, with the median time to cessation of viral shedding was approximately 3 days. _Recurrent genital herpes episodes_ The results of 3 separate studies of patients taking 3 to 5-day regimens of valacyclovir showed an average of 4 days to lesion healing, 2-3 days to resolution of pain associated with the lesions, with an average of 2 days until the cessation of viral shedding. These findings showed valacyclovir administration to show superior beneficial effects when compared to the findings associated with placebo administration. **A note on resistance** The resistance of Herpes Simplex Virus and Varicella Zoster Virus to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with decreased susceptibility to acyclovir have been isolated from patients diagnosed with AIDS. A total of 522 TK-deficient mutants of VZV have been identified in these cases. Absorption: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal (GI) tract and converted to acyclovir and L-valine. The absolute bioavailability of acyclovir after administration of valacyclovir was measured at 54.5% ± 9.1% after the administration of a 1 gram oral dose of valacyclovir and a 350 mg intravenous (IV) acyclovir dose to 12 healthy subjects. Acyclovir (a metabolite of valacyclovir) bioavailability from the administration of this drug is not affected by the administration with food. Biological Half-Life: The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in several studies of valacyclovir in volunteers with normal renal function. |
| Molecular Formula |
C13H20N6O4
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|---|---|
| Molecular Weight |
324.341
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| Exact Mass |
324.1546
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| Elemental Analysis |
C, 48.14; H, 6.22; N, 25.91; O, 19.73
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| CAS # |
124832-26-4
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| Related CAS # |
Valacyclovir hydrochloride;124832-27-5;Valacyclovir hydrochloride hydrate;1218948-84-5
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| PubChem CID |
135398742
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| Appearance |
Typically exists as solids (or liquids in special cases) at room temperature
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| Density |
1.5±0.1 g/cm3
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| Flash Point |
309.7ºC
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| Index of Refraction |
1.673
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| LogP |
-0.88
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| tPSA |
151.14
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| SMILES |
N[C@@H](C(C)C)C(OCCOCN1C=NC2=C1N=C(N)NC2=O)=O
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| InChi Key |
HDOVUKNUBWVHOX-QMMMGPOBSA-N
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| InChi Code |
InChI=1S/C13H20N6O4/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/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1
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| Chemical Name |
2-((2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy)ethyl L-valinate
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| Synonyms |
BW-256U87; BW-256; BW256256U87 hydrochloride; BW 256 Val-ACV; Valtrex; Zelitrex; Valacyclovir HCl; Valacyclovir hydrochloride; ValACV; Zelitrex; Valcivir; Valcyclovir; Val-ACV;
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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 | 3.0832 mL | 15.4159 mL | 30.8318 mL | |
| 5 mM | 0.6166 mL | 3.0832 mL | 6.1664 mL | |
| 10 mM | 0.3083 mL | 1.5416 mL | 3.0832 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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