Absorption, Distribution and Excretion
Valganciclovir is well absorbed from the gastrointestinal tract and the absolute bioavailability from valganciclovir tablets (following administration with food) is approximately 60%.
The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion.
0.703 ± 0.134 L/kg
3.07+/- 0.64 mL/min/kg [IV administration]
5.3 L/hr [Patient with creatinine clearance of 70.4 mL/min]
The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. Systemic clearance of intravenously administered ganciclovir was 3.07 + or - 0.64 mL/min/kg (n=68) while renal clearance was 2.99 + or - 0.67 mL/min/kg (n=16).
Due to the rapid conversion of valganciclovir to ganciclovir, plasma protein binding of valganciclovir was not determined. Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51 ug/mL. When ganciclovir was administered intravenously, the steady-state volume of distribution of ganciclovir was 0.703 + or - 0.134 L/kg (n=69). After administration of Valcyte tablets, no correlation was observed between ganciclovir AUC and reciprocal weight; oral dosing of Valcyte tablets according to weight is not required.
When Valcyte tablets were administered with a high fat meal containing approximately 600 total calories (31.1 g fat, 51.6 g carbohydrates and 22.2 g protein) at a dose of 875 mg once daily to 16 HIV-positive subjects, the steady-state ganciclovir AUC increased by 30% (95% CI 12% to 51%), and the Cmax increased by 14% (95% CI -5% to 36%), without any prolongation in time to peak plasma concentrations (Tmax). Valcyte should be administered with food.
The absolute bioavailability of ganciclovir following oral administration of valganciclovir is about tenfold higher than that following oral administration of ganciclovir (60 versus 5.6%, respectively). Results from pharmacokinetic studies in adults indicate that oral administration of valganciclovir 900 mg once daily with food provides a mean area under the plasma concentration-time curve 0-24 hour (AUC0-24 hour) for ganciclovir comparable to that following IV ganciclovir 5 mg/kg once daily and exceeding that following oral ganciclovir 1 g 3 times daily with food. However, at these dosages, oral valganciclovir produces lower peak plasma ganciclovir concentrations than IV ganciclovir, and lower trough plasma ganciclovir concentrations than oral ganciclovir. The clinical importance, if any, of these differences in peak and trough plasma drug concentrations with these 3 ganciclovir delivery systems has not been determined.
For more Absorption, Distribution and Excretion (Complete) data for Valganciclovir (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Rapidly hydrolyzed in the intestinal wall and liver to ganciclovir. No other metabolites have been detected.
Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. ...
Valganciclovir is rapidly hydrolyzed to ganciclovir; no other metabolites have been detected. No metabolite of orally administered radiolabeled ganciclovir (1000 mg single dose) accounted for more than 1% to 2% of the radioactivity recovered in the feces or urine.

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Biological Half-Life
Approximately 4.08 hours. Increased in patients with renal function impairment.
...Ten patients were evaluated. Patients were 56.8 + or - 3.4 years old and had a mean creatinine clearance of 69 + or - 9 mL/min. Oral bioavailability of ganciclovir after administration of valganciclovir was 59%, and mean half-life was 3.73 + or - 1.15 hours. ...
The terminal half-life of ganciclovir following oral administration of Valcyte tablets to either healthy or HIV-positive/CMV-positive subjects was 4.08 + or - 0.76 hours (n=73), and that following administration of intravenous ganciclovir was 3.81 + or - 0.71 hours (n=69). In heart, kidney, kidney-pancreas, and liver transplant patients, the terminal elimination half-life of ganciclovir following oral administration of Valcyte was 6.48 + or - 1.38 hours, and following oral administration of ganciclovir capsules was 8.56 + or - 3.62 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Valganciclovir is rapidly converted to ganciclovir. Several factors might affect the decision to use valganciclovir in a nursing mother. No information is available on the clinical use of ganciclovir or valganciclovir during breastfeeding. Cytomegalovirus (CMV) can be transmitted to infants though breastmilk, with preterm and immunocompromised infants at greatest risk. No information is available on any changes in the risk of transmission if the mother is being treated with ganciclovir or valganciclovir. Although the manufacturer recommends avoiding breastfeeding during valganciclovir use because of the risk of infant drug toxicity, neonates with CMV infections are often treated directly with ganciclovir or valganciclovir. If the mother has a concurrent infection with HIV, breastfeeding is not recommended in the United States and other developed countries.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Plasma protein binding of ganciclovir is 1% to 2% over concentrations of 0.5 and 51 mg/mL.

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Interactions
Potential pharmacologic interaction (additive hematologic toxicity (neutropenia, anemia)) /with concomitant use of valganciclovir and zidovudine.
Potential pharmacokinetic interaction /with concomitant use of valganciclovir and probenecid/ (decreased renal clearance and increased AUC of ganciclovir); monitor for ganciclovir toxicity.
Potential pharmacologic interactions (additive hematologic toxicity) /with concomitant use of valganciclovir and myelosuppressive agents or irradiation/.
Potential pharmacokinetic interaction /with concomitant use of valganciclovir and mycophenolate mofetil/ in patients with renal impairment (increased plasma concentrations of the metabolites of both drugs).
For more Interactions (Complete) data for Valganciclovir (6 total), please visit the HSDB record page.

[1]. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J Pharm Sci. 2000 Jun;89(6):781-9.

[2]. Oral valganciclovir versus ganciclovir as delayed pre-emptive therapy for patients after allogeneic hematopoietic stem cell transplant: a pilot trial (04-0274) and review of the literature. Transpl Infect Dis. 2012 Jun;14(3):259-67.

[3]. Valganciclovir prevents cytomegalovirus reactivation in patients receiving alemtuzumab-based therapy. Blood. 2008 Feb 15;111(4):1816-9.

Therapeutic Uses
Antiviral Agents
Valganciclovir hydrochloride tablets are used for initial (induction) treatment and maintenance treatment (secondary prophylaxis) of cytomegalovirus (CMV) retinitis in adults with human immunodeficiency virus (HIV) infection, including those with acquired immunodeficiency syndrome (AIDS). /Included in US product labeling/
The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) also recommend use of oral valganciclovir for treatment and secondary prophylaxis of CMV retinitis in HIV-infected older children and adolescents who can receive adult dosage. /NOT included in US product labeling/
Valganciclovir hydrochloride tablets are used for prevention of cytomegalovirus (CMV) disease in adult kidney, heart, and kidney-pancreas transplant recipients considered at high risk for the disease (CMV-seronegative recipient of an organ from a CMV-seropositive donor). /Included in US product labeling/
Cytomegalovirus (CMV) is the most common viral infection after solid organ transplantation (SOT). Safe and effective prophylactic regimens that decrease its incidence after SOT are essential for long-term graft survival. Although valganciclovir is not Food and Drug Administration-approved for CMV prophylaxis in liver transplant recipients, postmarketing studies have shown valganciclovir to be as effective as ganciclovir in high-risk adult patients undergoing SOT. Currently, data are lacking for pediatric liver transplantation. The purpose of this study was to compare the efficacy and safety of valganciclovir and ganciclovir for CMV infection prophylaxis in pediatric liver transplant recipients. This was a retrospective study of 56 pediatric liver transplant recipients who were prescribed either oral ganciclovir (n = 37) or valganciclovir (n = 19). Patients were followed until 200 days after transplantation or death. The primary outcome measure compared the rates of early-onset CMV infection and CMV disease in the 2 medication groups. Secondary outcome measures identified patient-specific factors that contributed to CMV acquisition and the incidence of late-onset CMV infection or disease. The rates of adverse drug effects and discontinuation were also evaluated. Early-onset CMV disease was documented in 0% of valganciclovir patients and in 5.4% of ganciclovir patients (P = 0.54). There were no statistically significant differences in the secondary outcomes. An increased incidence of late-onset CMV disease was seen in the valganciclovir group versus the ganciclovir group (22.2% versus 8.1%, P = 0.23). No differences in adverse events were reported. In conclusion, no statistically significant differences were found in the incidence of CMV infection or disease between patients receiving oral valganciclovir and patients receiving oral ganciclovir.

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Drug Warnings
/BOXED WARNING/ WARNING: HEMATOLOGIC TOXICITY, CARCINOGENICITY, TERATOGENICITY, AND IMPAIRMENT OF FERTILITY. Clinical toxicity of Valcyte, which is metabolized to ganciclovir, includes granulocytopenia, anemia, and thrombocytopenia. In animal studies, ganciclovir was carcinogenic, teratogenic, and caused aspermatogenesis.
Toxicity of valganciclovir, which is metabolized to ganciclovir, includes granulocytopenia, anemia, and thrombocytopenia. Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow aplasia, and aplastic anemia have been reported in patients receiving valganciclovir or ganciclovir. Cytopenia may occur at any time and the degree of cytopenia may increase with continued valganciclovir therapy. Cell counts usually begin to return to baseline 3-7 days after discontinuance of the drug. Complete blood cell counts (CBCs) and platelet counts should be performed frequently, especially in those with baseline neutrophil counts less than 1000/cu mm and in those who have experienced leukopenia while receiving ganciclovir or other nucleoside analogs. More frequent monitoring for cytopenias may be warranted if therapy is changed from oral ganciclovir to valganciclovir (because of comparatively increased plasma ganciclovir concentrations with valganciclovir). Valganciclovir should not be used in patients with an absolute neutrophil count less than 500/cu mm, a platelet count less than 25,000/cu mm, or a hemoglobin concentration less than 8 g/dL. Use with caution in patients with preexisting cytopenias and in those who have received or are receiving concomitant myelosuppressive drugs or irradiation.
Animal data indicate that ganciclovir is carcinogenic, mutagenic, teratogenic, and causes aspermatogenesis. Valganciclovir is converted to ganciclovir and is expected to have carcinogenic and reproductive toxic effects similar to those of ganciclovir. Valganciclovir can be considered a potential carcinogen in humans and may be teratogenic or embryotoxic at usual therapeutic doses. It is considered likely that valganciclovir will produce temporary or permanent inhibition of spermatogenesis and also may suppress fertility in females. Women of childbearing potential should be advised to use an effective method of contraception during and for at least 30 days after valganciclovir therapy. Men should be advised to use a reliable method of barrier contraception during and for at least 90 days after valganciclovir therapy.
Acute renal failure may occur in geriatric patients (with or without renal impairment), patients receiving potentially nephrotoxic drugs, and inadequately hydrated patients. Adequate hydration should be maintained in all patients. Use caution and adjust valganciclovir dosage based on creatinine clearance. Use caution in patients receiving concomitant therapy with potentially nephrotoxic drugs.
For more Drug Warnings (Complete) data for Valganciclovir (16 total), please visit the HSDB record page.

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Pharmacodynamics
Valganciclovir is an antiviral medication used to treat cytomegalovirus infections. As the L-valyl ester of ganciclovir, it is actually a prodrug for ganciclovir. After oral administration, it is rapidly converted to ganciclovir by intestinal and hepatic esterases. After this, it (being an analogue of guanosine) gets incorporated into DNA and thus cannot be properly read by DNA polymerase. This results in the termination of the elongation of viral DNA.

C14H22N6O5

354.36168

354.165

175865-60-8

Valganciclovir hydrochloride;175865-59-5;Valganciclovir-d5 TFA;1402924-31-5

135413535

Typically exists as solid at room temperature

1.6±0.1 g/cm3

629.1±65.0 °C at 760 mmHg

334.3±34.3 °C

0.0±1.9 mmHg at 25°C

1.678

-1.28

171.37

4

8

9

25

528

1

N[C@@H](C(C)C)C(OCC(OCN1C=NC2=C1N=C(N)NC2=O)CO)=O

WPVFJKSGQUFQAP-GKAPJAKFSA-N

InChI=1S/C14H22N6O5/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)/t8?,9-/m0/s1

[2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]-3-hydroxypropyl] (2S)-2-amino-3-methylbutanoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

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

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。