The primary molecular target of Valganciclovir is viral DNA polymerase, specifically the DNA polymerase of cytomegalovirus (CMV) and other herpesviruses. Valganciclovir is a prodrug of ganciclovir, which is a synthetic analog of 2'-deoxyguanosine. After oral administration, Valganciclovir is rapidly converted to ganciclovir by hepatic and intestinal esterases. Ganciclovir is then phosphorylated by viral (and to a lesser extent, cellular) kinases to ganciclovir monophosphate, which is further phosphorylated by cellular kinases to ganciclovir triphosphate (dGTP analog). Ganciclovir triphosphate competitively inhibits the incorporation of dGTP by viral DNA polymerase, leading to chain termination and inhibition of viral DNA synthesis. The selectivity of ganciclovir for viral DNA polymerase over cellular DNA polymerase is due to the preferential phosphorylation of ganciclovir by viral kinases and the higher affinity of viral DNA polymerase for ganciclovir triphosphate.

Valganciclovir hydrochloride is a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. After administration, these diastereomers are rapidly converted to ganciclovir by hepatic and intestinal esterases. In cytomegalovirus (CMV)-infected cells, ganciclovir is initially phosphorylated to the monophosphate form by viral protein kinase, then it is further phosphorylated via cellular kinases to produce the triphosphate form. This triphosphate form is slowly metabolized intracellularly. The phosphorylation is dependent upon the viral kinase and occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to the inhibition of viral DNA synthesis by ganciclovir triphosphate. Ganciclovir triphosphate is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand. Ganciclovir inhibits viral DNA polymerases more effectively than it does cellular polymerase, and chain elongation resumes when ganciclovir is removed.
In vitro activity of Valganciclovir is measured as its conversion to ganciclovir and subsequent antiviral activity. In cell-based antiviral assays using CMV-infected cells (e.g., human foreskin fibroblasts infected with CMV strain AD169 or Towne), ganciclovir (the active form of Valganciclovir) inhibits viral replication with EC50 values of 0.1-5 μM, depending on the CMV strain and the assay conditions. Valganciclovir itself shows similar activity in assays where cells are capable of converting the prodrug to the active form. Ganciclovir also shows activity against other herpesviruses, including herpes simplex virus (HSV-1, HSV-2) and varicella-zoster virus (VZV), though with different potency. In cytotoxicity assays using uninfected cells, ganciclovir shows CC50 values typically >100 μM, indicating a favorable selectivity index. The compound's activity is time-dependent, with prolonged incubation required for optimal antiviral effects. Ganciclovir-resistant CMV strains can emerge through mutations in the UL97 gene (which encodes the viral kinase responsible for ganciclovir phosphorylation) or in the UL54 gene (which encodes viral DNA polymerase).

After oral administration, intestinal and hepatic esterases hydrolyze both diastereomers to ganciclovir, which inhibits replication of the human cytomegalovirus. Valganciclovir is well absorbed from the gastrointestinal tract and the absolute bioavailability from valganciclovir tablets (following administration with food) is approximately 60%.
In vivo activity of Valganciclovir has been demonstrated in clinical studies for the treatment of CMV infections. Valganciclovir is used for the treatment of CMV retinitis in patients with AIDS and for the prevention of CMV disease in high-risk solid organ transplant recipients. In clinical studies, oral Valganciclovir (900 mg twice daily) provides comparable efficacy to intravenous ganciclovir (5 mg/kg twice daily) for the treatment of CMV retinitis. In transplant recipients, Valganciclovir prophylaxis (900 mg once daily for 100 days) reduces the incidence of CMV disease. The prodrug formulation provides significantly improved oral bioavailability compared to ganciclovir, allowing for oral administration instead of intravenous infusion. The compound's conversion to ganciclovir by hepatic and intestinal esterases ensures that the active drug is delivered systemically. The compound's efficacy is dose-dependent, with higher doses providing better antiviral activity but also increased toxicity.

For in vitro antiviral assays with ganciclovir and Valganciclovir, the following protocol is used: human foreskin fibroblasts (HFF) or MRC-5 cells are cultured in DMEM with 10% FBS and antibiotics at 37°C in 5% CO₂. Cells are seeded in 96-well plates at 1-2 × 10⁴ cells per well and grown to confluence. CMV (e.g., AD169 or Towne strain) is diluted to 100-1000 PFU and added to the cells. The test compound (ganciclovir or Valganciclovir) is serially diluted in culture medium to final concentrations ranging from 0.001 to 100 μM. The cells are incubated at 37°C for 5-7 days. Viral replication is assessed by plaque reduction assay (plates are stained with crystal violet or neutral red), by immunofluorescence staining for CMV antigens (e.g., immediate early antigen), or by qPCR for CMV DNA. EC50 values are calculated from dose-response curves using nonlinear regression. Cytotoxicity is assessed in parallel using uninfected cells with the MTT assay to calculate CC50 and selectivity index. For drug combination studies, the compound is tested in combination with other antiviral agents (e.g., foscarnet, cidofovir) using the checkerboard method or the time-kill method. For resistance studies, CMV isolates with known mutations in UL97 or UL54 are tested to determine the compound's activity against resistant strains.

For in vitro cell-based assays with ganciclovir and Valganciclovir, the following typical protocol is used: for studies on phosphorylation and metabolism, cells are treated with [³H]ganciclovir or [³H]Valganciclovir, and the intracellular concentrations of ganciclovir, ganciclovir monophosphate, diphosphate, and triphosphate are measured by HPLC or LC-MS/MS. For studies on DNA polymerase inhibition, the incorporation of [³H]dGTP into DNA in the presence of ganciclovir triphosphate is measured using purified viral DNA polymerase and a DNA template. For studies on cell cycle effects, cells are treated with ganciclovir and analyzed by flow cytometry after propidium iodide staining. For studies on apoptosis, cells are stained with Annexin V-FITC and propidium iodide and analyzed by flow cytometry. For cytotoxicity studies, various cell lines (e.g., HFF, HepG2, HEK293) are treated with the compound for 24-72 hours, and cell viability is assessed by MTT or CellTiter-Glo assay.

For in vivo animal studies with Valganciclovir, the following general protocol is used: for CMV infection models, immunocompromised mice (e.g., SCID mice or mice treated with immunosuppressive drugs) are infected with murine CMV (MCMV) or human CMV (in humanized mouse models). Valganciclovir is administered orally or by gavage at doses of 10, 30, and 100 mg/kg once or twice daily for 7-14 days. Viral loads in tissues (liver, spleen, lungs, salivary glands) are measured by plaque assay or qPCR. Survival is monitored for 14-28 days. For pharmacokinetic studies, blood samples are collected at various time points after oral administration, and plasma concentrations of Valganciclovir and ganciclovir are analyzed by LC-MS/MS. Tissue distribution studies are performed to determine the concentrations of the drug in target organs (liver, kidney, lungs, eyes). For toxicology studies, animals are treated with the compound for up to 28 days, and clinical chemistry, hematology, and histopathology are assessed.

The pharmacokinetic properties of Valganciclovir are well-characterized in humans. After oral administration, Valganciclovir is rapidly absorbed and converted to ganciclovir by hepatic and intestinal esterases. The oral bioavailability of ganciclovir from Valganciclovir is approximately 60%, compared to approximately 6% for oral ganciclovir. Peak plasma concentrations of ganciclovir are reached within 1-3 hours (Tmax). The compound's volume of distribution is approximately 0.8-1.0 L/kg, similar to total body water. Plasma protein binding is low (approximately 1-2%). The elimination half-life of ganciclovir after Valganciclovir administration is approximately 4-6 hours in patients with normal renal function. Ganciclovir is primarily excreted unchanged in the urine (approximately 80-90%) by glomerular filtration and tubular secretion. Dose adjustment is required in patients with renal impairment. The compound's pharmacokinetics are linear over the therapeutic dose range. Food intake increases the absorption of Valganciclovir, and it is recommended to be taken with meals.

The toxicity profile of Valganciclovir is well-established from clinical use. The most common adverse effects include gastrointestinal disturbances (nausea, vomiting, diarrhea), headache, and fatigue. More serious adverse effects include myelosuppression (neutropenia, anemia, thrombocytopenia), which is dose-dependent and more common in immunocompromised patients. Valganciclovir is contraindicated in patients with known hypersensitivity to ganciclovir or Valganciclovir. It should be used with caution in patients with renal impairment (dose adjustment required), hematological disorders, and in pregnant women (category C). In animal studies, ganciclovir has been shown to be teratogenic and embryotoxic, and Valganciclovir is not recommended during pregnancy unless the potential benefit justifies the potential risk to the fetus. The compound is also mutagenic and carcinogenic in animal studies, though these effects are primarily related to the mechanism of action (inhibition of DNA synthesis). Valganciclovir is not recommended for use in children unless the potential benefit justifies the potential risk.

[1]. J Pharm Sci.2000 Jun;89(6):781-9;
[1]. Drugs.2005;65(6):859-78.

Valganciclovir hydrochloride is an antiviral prescription drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of cytomegalovirus retinitis (CMV retinitis) in adults with HIV/AIDS. Valganciclovir hydrochloride is also FDA-approved for the prevention of CMV infection in organ transplant recipients (who are at risk of CMV infection). CMV infection, including CMV retinitis, can be an opportunistic infection (OI) of HIV. Valganciclovir hydrochloride is the hydrochloride form of valganciclovir, a prodrug of ganciclovir, a 2'-deoxyguanosine nucleoside analog with antiviral activity. Upon phosphorylation, valganciclovir is incorporated into DNA, thereby inhibiting viral DNA polymerase and thus viral replication. Valganciclovir is a ganciclovir prodrug and antiviral drug used to treat cytomegalovirus retinitis in patients with HIV/AIDS and to prevent cytomegalovirus infection in patients who have received organ transplants from cytomegalovirus-positive donors. See also: valganciclovir (its salt form).
Valganciclovir HCl (CAS# 175865-59-5) is the L-valyl ester prodrug of ganciclovir used to treat CMV infection. It has a molecular formula of C14H22N6O5·HCl and a molecular weight of 390.82 g/mol. It is phosphorylated to a dGTP analog that inhibits viral DNA polymerase. Future research could focus on developing new formulations to improve bioavailability and reduce toxicity, investigating its activity against ganciclovir-resistant CMV strains, and exploring its potential in combination with other antiviral agents.

C14H22N6O5.HCL

390.825

390.141

C, 43.03; H, 5.93; Cl, 9.07; N, 21.50; O, 20.47

175865-59-5

Valganciclovir;175865-60-8;Valganciclovir-d8 hydrochloride;1132088-63-1

135413534

White to light yellow solid powder

629.1ºC at 760 mmHg

1.08E-16mmHg at 25°C

0.646

5

8

9

26

528

1

Cl[H].O(C([H])([H])N1C([H])=NC2C(N([H])C(N([H])[H])=NC1=2)=O)C([H])(C([H])([H])O[H])C([H])([H])OC([C@]([H])(C([H])(C([H])([H])[H])C([H])([H])[H])N([H])[H])=O

ZORWARFPXPVJLW-MTFPJWTKSA-N

InChI=1S/C14H22N6O5.ClH/c1-7(2)9(15)13(23)24-4-8(3-21)25-6-20-5-17-10-11(20)18-14(16)19-12(10)22;/h5,7-9,21H,3-4,6,15H2,1-2H3,(H3,16,18,19,22);1H/t8?,9-;/m0./s1

[2-[(2-amino-6-oxo-3H-purin-9-yl)methoxy]-3-hydroxypropyl] (2S)-2-amino-3-methylbutanoate hydrochloride

RS 079070-194; RO 107-9070/194; RS-79070-194; RS-079070-194; ganciclovir L-valyl ester; Valganciclovir HCl; Cymeval; Valcyt; Valixa; Darilin; Rovalcyte; Patheon

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.40 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.40 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.40 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (255.87 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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