更昔洛韦 (BW 759) 是一种无环脱氧鸟苷类似物，化学性质与阿昔洛韦相似，但对抗 CMV 更有效。抑制病毒复制 50% 所需的更昔洛韦中位浓度为 2.15 μM，而阿昔洛韦为 72 μM [4]。更昔洛韦抗 CMV 的主要机制是通过更昔洛韦-5'-三磷酸盐（更昔洛韦-TP）抑制病毒 DNA 复制。这种抑制涉及对病毒 DNA 聚合酶的特异性和强烈抑制。更昔洛韦主要通过三种细胞酶转化为三磷酸形式：CMV 感染细胞产生的脱氧鸟苷激酶、鸟苷酸激酶和磷酸甘油酸激酶[5]。

更昔洛韦 (BW 759)（50 mg/kg；腹腔注射；每天两次，共五次注射）可以扩散到大脑和内耳的外淋巴区域，并显着减少新生小鼠的白细胞、红细胞和血小板[3 ]。更昔洛韦（1-80 mg/kg；静脉注射；每天一次，持续 5 天）可以推迟由鼠巨细胞病毒 (MCMV) 引起的发病和消耗综合征[6]。

Animal/Disease Models: Non-inbred Oncins France 1 (OF1) mice and albino rats non-immunized for MCMV[3]
Doses: 50 mg/kg
Route of Administration: intraperitoneal (ip)injection, twice a day for five injections (mice) or 3 days (adult rats) (pharmacokinetic/PK Study)
Experimental Results: In adult rats, the intracochlear diffusion of Ganciclovir was shown to achieve the same concentration as in blood. In gestating mice, transplacental diffusion was observed, with a fetal-to-maternal blood ratio of 0.5. In newborn mice, the plasma concentration profile of Ganciclovir demonstrated a peak at 2 h followed by a gradual decrease. In adult mice, the concentration peaked at 1 h, but became undetectable by 2 h after injection. Dramatically diminished white blood cells, red blood cells and platelets in newborn mice.

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Animal/Disease Models: Female SCID (severe combined immunodeficient) mouse inoculated with MCMV[6]
Doses: 0, 1, 10, 80 and 160 mg/kg
Route of Administration: subcutaneous (sc) injection, one time/day for 5 days
Experimental Results: Dose dependently delayed the wasting syndrome and mortality in a dose

Absorption, Distribution and Excretion
Poorly absorbed systemically following oral administration. Bioavailability under fasting conditions is approximately 5%, and when administered with food, 6 to 9% (about 30% with a fatty meal).
Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir.
0.74 ± 0.15 L/kg
128 +/- 63 mL/min [Patients with Renal Impairment (Clcr=50-79 mL/min)]
57+/- 8 mL/min [Patients with Renal Impairment (Clcr=25-49 mL/min)]
30 +/- 13 mL/min [Patients with Renal Impairment (Clcr<25 mL/min)]
4.7+/- 2.2 mL/min/kg [pediatric patients, aged 9 months to 12 years]
Ganciclovir is absorbed poorly from the GI tract. Following oral administration of an aqueous solution of ganciclovir sodium, 7% or less of a 10 to 20 mg/kg dose appears to be absorbed, based on urinary recovery, and relative oral bioavailability appears to decrease with increasing dose and multiple administration. Plasma ganciclovir concentrations required for therapeutic antiviral activity currently are not known. Although peak plasma ganciclovir concentrations achieved after oral administration of 20 mg/kg every 6 hr have exceeded the in vitro ID50 (concentration of the drug required to produce 50% inhibition of viral plaque formation) of many strains of cytomegalovirus, the ID50 for many other susceptible strains of the virus exceed peak plasma concentrations achievable with this oral dosage; therefore, iv administration of the drug currently is preferred. In a study in several adults with acquired immunodeficiency syndrome and cytomegalovirus retinitis receiving an oral ganciclovir dosage of 20 mg/kg every 6 hr, peak plasma concentrations of the drug were achieved within 1 hr and averaged about 0.76 ug/ml at steady state; steady state trough plasma concentrations prior to a dose averaged about 0.27 g/ml. /Ganciclovir sodium/
In a limited number of immunocompromised patients with cytomegalovirus infections and normal renal function who received a ganciclovir dosage of 5 mg/kg every 12 hr by iv infusion over 1 hr, peak plasma concentrations of the drug obtained at the end of the infusion and averaged 9.5-11.6 ug/ml (range: 3.1-24.1 ug/ml) and trough plasma concentrations obtained just prior to a dose averaged 1.6 ug/ml (range: 0.11-3.5 ug/ml). Somewhat lower peak and trough concentrations (averaging 6.6-8.3 and 0.56-1 ug/ml, respectively) were achieved after the first dose. Peak and trough plasma concentrations of the drug following iv infusion over 1 hr of 2.5 mg/kg every 8 hr averaged 4.09-5.36 (range: 1.66-7.78 ug/ml) and 0.33-1.07 ug/ml (range: 0.2-1.66 ug/ml), respectively, in immunocompromised patients with cytomegalovirus infections and normal renal function. In a limited number of such patients receiving 5 mg/kg every 8 hr by iv infusion over 1 hr, peak and trough plasma concentrations averaged 6.53-11.41 and 1.13-2.23 ug/ml, respectively. Accumulation of the drug does not appear to occur in patients with normal renal function receiving iv dosages of 3-15 mg/kg daily in divided doses. /Ganciclovir sodium/
Limited data suggest that minimal systemic absorption of ganciclovir occurs following intravitreal injection of the drug, although adequate intravitreal ganciclovir concentrations appear to be achievable with such administration. In a patient with cytomegalovirus retinitis receiving five 200 ug intravitreal doses over 15 days, systemic plasma ganciclovir concentrations achieved during therapy were less than 0.1 ug/ml. A vitreous humor concentration of 1.17 ug/ml and an aqueous humor concentration of 0.66 ug/ml were achieved 51.4 hr after the initial dose in this patient, and a vitreous humor concentration of 0.1 ug/ml was achieved 97.3 hr after the fourth dose. Data from rabbits also indicate that antiviral intravitreal concentrations of the drug are achievable with small intravitreal but not subconjunctival doses of ganciclovir. Following intravitreal injection of a single 400 ug dose in rabbits, vitreous humor ganciclovir concentrations averaged 543, 423, 57.7, 16, 2.02, and 1.2 ug/ml 2, 5, 12, 24, 48, and 60 hr after injection. Following subconjunctival injection of a single 1.25-mg dose in rabbits, ganciclovir concentrations 1, 2, 3, and 8 hr after injection averaged 0.09, 0.31, 0.16, and 0.02 ug/ml, respectively, in vitreous humor and 2.18, 3.27, 2.22, and 0.07 ug/ml, respectively, in aqueous humor. /Ganciclovir sodium/
Distribution of ganciclovir into human body tissues and fluids has not been fully elucidated. Autopsy findings in several patients receiving the drug iv suggest that ganciclovir concentrates in the kidney, with substantially lower concentrations occurring in lung, liver, brain, and testes. While efficacy of the drug in cytomegalovirus pneumonitis has been substantially less than in many other infections (eg, retinitis) with the virus to date, lung ganciclovir concentrations that exceed the ID50 for cytomegalovirus appear to be achievable with usual iv dosages. Concentrations attained in lung and liver were 99 and 92%, respectively, of those attained concurrently in heart blood in several adults receiving the drug iv. Following iv administration in mice, ganciclovir was distributed widely, achieving highest concentrations in the kidney and lowest concentrations in the brain. Substantial distribution of ganciclovir into lung, liver, heart, spleen, stomach, intestines, muscle, and testes also occurred, exceeding concurrent blood concentrations in these tissues; concentrations achieved in brain, eyes, and fat were lower than concurrent blood concentrations. Accumulation of the drug did not appear to occur, although measurable concentrations persisted for at least 30 hr in stomach, liver, and intestines in these animals. In addition, there was no evidence of testicular ganciclovir accumulation in several humans receiving 15 mg/kg iv daily for 8-13 days.
For more Absorption, Distribution and Excretion (Complete) data for GANCICLOVIR (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
Little to no metabolism, about 90% of plasma ganciclovir is eliminated unchanged in the urine.
With the exception of intracellular phosphorylation of the drug, ganciclovir does not appear to be metabolized appreciably in humans.

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Biological Half-Life
2.5 to 3.6 hours (mean 2.9 hours) when administered intravenously in adults. 3.1 to 5.5 hours when administered orally in adults. Renal function impairment causes a marked increase in half life (9 to 30 hours intravenously, 15.7 to 18.2 hours orally).
Plasma concentrations of ganciclovir appear to decline in a biphasic manner. In adults with normal renal function, the half-life of ganciclovir in the initial distribution phase averages 0.23-0.76 hr and the half-life in the terminal elimination phase averages 2.53-3.6 hr. Plasma concentrations of the drug may be higher and the elimination half-life prolonged in patients with impaired renal function. In adults with moderate to severe renal impairment (creatinine clearances less than 50 ml/min/1.73 sq m), the terminal half-life of ganciclovir ranged from 4.4-30 hr, depending on the degree of impairment.
The elimination half-life of ganciclovir from the vitreous humor after intravitreal injection was estimated to be 13.3 hr in a patient with cytomegalovirus retinitis.
In rabbits, the elimination half-life from vitreous humor after intravitreal injection of a single 400 ug dose was 8.6 hr.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Several factors might affect the decision to use ganciclovir in a nursing mother. No information is available on the clinical use of ganciclovir 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. Although the manufacturer recommends avoiding breastfeeding during ganciclovir use because of the risk of infant drug toxicity, neonates with CMV infections are often treated directly with ganciclovir. 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
1 to 2%

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Interactions
Results of an in vitro study using H9 cells inoculated with HIV (strain HTLV-IIIB) indicate that ganciclovir antagonizes the antiretroviral activity of didanosine against HIV.
Results of an in vitro study using H9 cells inoculated with HIV (strain HTLV-IIIB) indicate that ganciclovir antagonizes the antiretroviral activity of zidovudine against HIV. ... Concomitant use of zidovudine with ganciclovir can increase the risk of hematologic toxicity. Both zidovudine and ganciclovir alone produce direct, dose-dependent inhibitory effects on myeloid and erythroid progenitor cells, and combined use of the drugs may result in additive or synergistic myelotoxic effects. In several studies in patients with AIDS and cytomegalovirus infections, profound, intolerable myelosuppression, evidenced principally as severe neutropenia, occurred in all patients receiving zidovudine (200 mg orally every 4 hr) concomitantly with ganciclovir (5 mg/kg iv 1-4 times daily); anemia also occurred in many of these patients. Severe hematologic toxicity, which required a reduction in zidovudine dosage, also occurred in more than 80% of patients receiving zidovudine (100 mg orally every 4 hr) concomitantly with ganciclovir (5 mg/kg iv 1-2 times daily). Several other patients with initially stable hematologic findings on ganciclovir alone, developed prolonged pancytopenia during concomitant therapy with oral zidovudine and iv ganciclovir. The increased risk of hematologic toxicity does not appear to be related to a pharmacokinetic interaction between ganciclovir and zidovudine since there is no evidence that concomitant use affects the pharrnacokinetic parameters of either drug.
Foscarnet has exhibited additive or synergistic antiviral activity with ganciclovir in vitro and/or in vivo against cytomegalovirus and herpes simplex virus type 2. In addition, combined therapy with the drugs may be effective in the treatment of cytomegalovirus infection resistant to either drug alone.
Although renal excretion of ganciclovir appears to occur principally via glomerular filtration, limited renal secretion of the drug also may occur. Therefore, ... the possibility that probenecid or other drugs that inhibit renal tubular secretion or reabsorption may interfere with the renal clearance and urinary excretion of ganciclovir should be considered.
For more Interactions (Complete) data for GANCICLOVIR (10 total), please visit the HSDB record page.

[1]. Ganciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs. 1990;39(4):597-638.

[2]. In vitro efficacy of ganciclovir, cidofovir, penciclovir, foscarnet, idoxuridine, and acyclovir against feline herpesvirus type-1. Am J Vet Res. 2004 Apr;65(4):399-403.

[3]. Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats. Antiviral Res. 2016;132:111-115.

[4]. Evaluation of ganciclovir for cytomegalovirus disease. DICP. 1989 Jan;23(1):5-12.

[5]. Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis. 1988 Jul-Aug;10 Suppl 3:S490-4.

[6]. Duan J, Paris W, Kibler P, Bousquet C, Liuzzi M, Cordingley MG. Dose and duration-dependence of ganciclovir treatment against murine cytomegalovirus infection in severe combined immunodeficient mice. Antiviral Res. 1998;39(3):189-197.

Therapeutic Uses
Antiviral Agents
IV ganciclovir is used for the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). ... Some clinicians suggest that IV ganciclovir, IV foscarnet, IV cidofovir, oral valganciclovir, or intravitreal fomivirsen currently are appropriate initial choices for induction and maintenance therapy of CMV retinitis. ... Ganciclovir also has been used for the treatment of other cytomegalovirus infections (eg, GI infections, pneumonitis) in immunocompromised patients, but experience with the drug in these extraocular infections is less extensive, and safety and efficacy remain to be established. Despite this lack of experience inextraocular infections, ganciclovir has been considered the drug of choice for cytomegalovirus infections when antiviral therapy is warranted. While the safety and efficacy of ganciclovir compared with foscarnet for the treatment of cytomegalovirus infections other than retinitis remain to be established, some clinicians state that pending further accumulation of data, ganciclovir may offer some advantages over foscarnet secondary to patient tolerance and patient acceptability, and the choice of antiviral agent for cytomegalovirus infections should be individualized.

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Drug Warnings
Patients allergic to acyclovir may also be allergic to ganciclovor because of chemial similarity of the 2 medications.
Because ganciclovir therapy frequently is associated with hematologic toxicity, principally neutropenia and/or thrombocytopenia, blood cell counts should be monitored frequently. Patients should be informed of the potential hematologic toxicities of the drug and of the importance of close monitoring of blood cell counts. Neutrophil and platelet counts should be performed several times weekly (every other day or 2 or 3 times weekly) during iv induction therapy with the drug and at least weekly thereafter during maintenance therapy. More frequent monitoring is recommended for patients who have previously experienced leukopenia with ganciclovir or another nucleoside analog or in whom neutrophil counts are less than 1000/cu mm prior to initiating therapy with the drug; the manufacturer recommends that neutrophil counts be monitored daily in such patients. However, some clinicians state that less frequent monitoring (eg, twice weekly) may be sufficient in such patients during maintenance therapy. Also, it is recommended that neutrophil and platelet counts be monitored daily in patients undergoing hemodialysis. If neutropenia and/or thrombocytopenia occur, dosage adjustment and/or interruption of ganciclovir therapy may be necessary.
Ganciclovir should be used with caution in patients with preexisting cytopenias or a history of cytopenic reactions to other drugs, chemicals, or radiation therapy. In addition, /it is/ recommended that parenteral ganciclovir therapy not be administered to patients whose absolute neutrophil count is less than 500/cu mm or whose platelet count is less than 25,000/cu mm. Because the drugs may have additive or synergistic hematologic toxicity, the concomitant use of ganciclovir and zidovudine currently is not recommended; however, modified regimens with the drugs occasionally have been employed with extreme caution. AIDS patients should be counseled about the possible risks of combined therapy with the drugs, and the decision to discontinue zidovudine and initiate ganciclovir should be made by the patient and clinician, carefully weighing the potential risks and benefits.
Parenteral ganciclovir therapy should be accompanied by adequate patient hydration since the drug is almost entirely excreted renally and normal clearance depends on adequate renal function. Ganciclovir should be used with caution and at reduced dosage in patients with impaired renal function. In addition, because of the importance of adequate renal function in eliminating the drug, the manufacturer recommends that serum creatinine or creatinine clearance be determined at least every other week in all patients receiving the drug parenterally and that necessary adjustments in dosage be made if abnormalities are observed. Because impaired renal function has been reported frequently in controlled studies evaluating use of ganciclovir in transplant recipients, patients receiving ganciclovir for prevention of cytomegalovirus disease after transplantation, especially those receiving concomitant therapy with potentially nephrotoxic drugs (eg, cyclosporine, amphotericin B), should be counseled regarding the possibility of this adverse effect.
For more Drug Warnings (Complete) data for GANCICLOVIR (15 total), please visit the HSDB record page.

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Pharmacodynamics
Ganciclovir is a synthetic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Sensitive human viruses include cytomegalovirus (CMV), herpes simplex virus -1 and -2 (HSV-1, HSV-2), Epstein-Barr virus (EBV) and varicella zoster virus (VZV), however clinical studies have been limited to assessment of efficacy in patients with CMV infection. Ganciclovir is a prodrug that is structurally similar to acyclovir. It inhibits virus replication by its encorporation into viral DNA. This encorporation inhibits dATP and leads to defective DNA, ceasing or retarding the viral machinery required to spread the virus to other cells.

C9H13N5O4

255.23

255.096

C, 42.35; H, 5.13; N, 27.44; O, 25.07

82410-32-0

Ganciclovir sodium;107910-75-8;Ganciclovir-d5;1189966-73-1;Ganciclovir hydrate;1359968-33-4

135398740

White to off-white solid powder

1.8±0.1 g/cm3

657.0±65.0 °C at 760 mmHg

250°C

351.1±34.3 °C

0.0±2.1 mmHg at 25°C

1.761

-3.62

139.28

4

6

5

18

346

0

O=C1C2N=CN(C=2NC(N)=N1)COC(CO)CO

IRSCQMHQWWYFCW-UHFFFAOYSA-N

InChI=1S/C9H13N5O4/c10-9-12-7-6(8(17)13-9)11-3-14(7)4-18-5(1-15)2-16/h3,5,15-16H,1-2,4H2,(H3,10,12,13,17)

2-amino-1,9-dihydro-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one

2'-Nor-2'-deoxyguanosine, BW-759 BW 759

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)

DMSO : ~60 mg/mL (~235.08 mM)
H2O : ~1.67 mg/mL (~6.54 mM)

配方 1 中的溶解度: 2.08 mg/mL (8.15 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: 2.08 mg/mL (8.15 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (8.15 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 3.33 mg/mL (13.05 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶 (<60°C).

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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。