Viral DNA polymerase (herpesviruses, including human cytomegalovirus [HCMV], herpes simplex virus type 1 [HSV-1], herpes simplex virus type 2 [HSV-2]; EC50 for HCMV: 0.1-0.3 μM, HSV-1: 0.5-1.0 μM, HSV-2: 0.8-1.2 μM) [1]
- Viral DNA synthesis (adenoviruses; EC50: 0.2-0.5 μM) [4]
- Viral replication (poxviruses; EC50: 0.15-0.4 μM) [2]

西多福韦抑制培养细胞中的人巨细胞病毒 (HCMV) 感染。即使在感染后 48 小时添加到细胞中，西多福韦也能抑制 CMV 斑块形成，对于 Davis 菌株和 AD-169 菌株的 IC50 分别为 0.9 μg/mL 和 1.6 μg/mL。西多福韦还抑制单纯疱疹病毒感染。此外，Cidofovir 还可阻断猴肾细胞中 HSV-1 诱导的细胞融合，并阻断 HSV-1 特异性蛋白的表达和病毒 DNA 的合成。

---

在人包皮成纤维细胞（HFF）中抑制HCMV复制，EC50为0.2 μM；对实验室菌株和临床HCMV菌株均表现出强效活性，且在有效浓度下无明显细胞毒性[1]
- 在Vero细胞中抑制HSV-1和HSV-2复制，EC50分别为0.7 μM和1.0 μM；活性呈浓度依赖性，且在给药后72小时仍持续有效[1]
- 在HeLa细胞中抑制5型腺病毒复制，EC50为0.3 μM；1 μM浓度下可使病毒DNA合成减少90%[4]
- 在BSC-1细胞中对牛痘病毒（痘病毒）发挥抗病毒活性，EC50为0.25 μM；0.5 μM浓度下可抑制80%的病毒空斑形成[2]
- 在哺乳动物细胞（HFF、Vero、HeLa）中细胞毒性极低，CC50＞100 μM，对HCMV的选择性指数（SI）＞300[1]
- 在无细胞实验中抑制HCMV的病毒DNA聚合酶活性，Ki为0.05 μM；与脱氧胞苷三磷酸（dCTP）竞争结合该酶[3]

西多福韦（5 mg/kg/天）皮下注射 5 天可显着降低受感染豚鼠血液、脾脏、肺和唾液腺中的平均病毒感染滴度。西多福韦显着降低受感染动物的淋巴细胞增多和脾脏平均组织指数。西多福韦可抑制皮内感染 HSV-1 或 HSV-2 的无毛小鼠的所有表现（皮肤损伤、后腿麻痹和死亡）。西多福韦最显着的特点是，即使在感染后 4 天，单次施用该化合物也能显着预防 HSV-1 或 HSV-2 感染。西多福韦可抑制由皮下移植到 C57B16/J 小鼠体内的小鼠黑色素瘤 B16 细胞产生的高度侵袭性黑色素瘤的生长。

---

降低感染HCMV的严重联合免疫缺陷（SCID）小鼠的死亡率；每3天腹腔注射（i.p.）20 mg/kg，持续2周，可使组织病毒载量降低95%[1]
- 抑制无毛小鼠中HSV-1诱导的皮肤损伤；每日2次局部涂抹1%制剂，持续5天，可使损伤面积缩小70%，愈合时间缩短3天[5]
- 提高牛痘病毒感染小鼠的存活率；感染后第1、3、5天腹腔注射15 mg/kg，存活率达80%，而对照组存活率仅为20%[2]

从感染HCMV的HFF细胞中部分纯化病毒DNA聚合酶；将该酶与不同浓度的西多福韦（0.01-10 μM）、dCTP（10 μM）和活化小牛胸腺DNA（模板）共同孵育；通过检测[3H]-dATP掺入酸不溶性物质的量来测定DNA合成；基于Lineweaver-Burk图计算Ki值[3]
- 利用纯化的酶在体外检测HSV-1 DNA聚合酶活性；将酶与西多福韦（0.05-5 μM）、dNTP底物（包括[α-32P]-dCTP）和poly(dA-dT)模板混合；通过放射自显影检测放射性标记的DNA产物并定量，以确定抑制效率[1]

细胞系：Crandell-Reese 猫肾 (CRFK) 细胞
浓度：10-100 μM
孵育时间：72 小时
结果：CRFK 细胞减少 9.1%。

---

在96孔板中接种HFF细胞，每孔1×104个；过夜贴壁后，以感染复数（MOI）0.1的HCMV感染细胞；感染后2小时加入0.01-10 μM的西多福韦；孵育7天后，通过间接免疫荧光染色检测HCMV早期抗原以评估病毒复制；将抑制50%抗原阳性细胞的浓度定为EC50[1]
- 在24孔板中培养Vero细胞；以MOI=0.05的HSV-1感染细胞；感染后立即加入0.1-5 μM的西多福韦；孵育48小时后，用福尔马林固定细胞，结晶紫染色观察病毒空斑；计数空斑并计算相对于未处理对照组的抑制率[1]
- 在6孔板中接种HeLa细胞；以MOI=1的5型腺病毒感染细胞；感染后1小时暴露于0.05-2 μM的西多福韦；感染后48小时收集细胞，分离病毒DNA；通过斑点杂交定量病毒基因组拷贝数；基于拷贝数减少量确定EC50[4]

Female weanling BALB/c mice infected with cowpox virus (CPV)
100 mg/kg
Subcutaneous injection; 3-6 days interval; 21 days

---

SCID mice (6-8 weeks old) were inoculated intravenously (i.v.) with 5×106 HCMV-infected HFF cells; Cidofovir was dissolved in phosphate-buffered saline (PBS) and administered i.p. at doses of 5, 10, or 20 mg/kg every 3 days for 2 weeks; control mice received PBS alone; mice were monitored for survival and tissue viral load (quantified by viral plaque assay) [1]
- Hairless mice (8-10 weeks old) were inoculated intradermally (i.d.) with 1×105 PFU of HSV-1 on the dorsal skin; Cidofovir was formulated as a 1% cream in petrolatum; applied topically to lesions twice daily for 5 days, starting 24 hours post-infection; lesion size was measured daily, and healing time was recorded [5]
- BALB/c mice (6 weeks old) were infected i.p. with 1×104 PFU of vaccinia virus; Cidofovir was dissolved in PBS and administered i.p. at 15 mg/kg on days 1, 3, and 5 post-infection; control mice received PBS; survival was monitored for 14 days [2]

Absorption, Distribution and Excretion
100%
537 ± 126 mL/kg [VISTIDE ADMINISTERED WITHOUT PROBENECID]
410 ± 102 mL/kg [VISTIDE ADMINISTERED WITH PROBENECID]
179 +/- 23.1 mL/min/1.73 m2 [WITHOUT PROBENECID]
148 +/- 38.8 mL/min/1.73 m2 [WITH PROBENECID]
Volume of distribution is 537 ml/kg without concurrent probenecid administration and 410 ml/kg with concurrent probenecid administration.
Concentrations of cidofovir were undetectable 15 minutes after the end of a 1 hour infusion in one patient who had a corresponding serum concentration of 8.7 ug/mL.
Renal (without concurrent probenecid administration): Approximately 80 to 100% of an administered cidofovir dose was recovered unchanged in the urine within 24 hours.
Cidofovir is dianionic at physiological pH and have low oral bioavailability in animals and humans. After intravenous administration to HIV-infected patients, the pharmacokinetics of /cidofovir is/ independent of dose and are consistent with preclinical data. Systemic exposure is proportional to the intravenous dose and /the drug is cleared/ by the kidney and excreted extensively as unchanged drug in the urine. Intracellular activation of a small fraction (< 10%) of the dose by cellular kinases leads to prolonged antiviral effects that are not easily predicted from conventional pharmacokinetic studies. The observed rate of elimination of cidofovir ... from the serum may not reflect the true duration of action of these drugs, since the antiviral effect is dependent on concentrations of the active phosphorylated metabolites that are present within cells. For /cidofovir/, > 90% of an iv dose is recovered unchanged in the urine over 24 hours.
This study was undertaken to evaluate the intravitreal and plasma concentrations of cidofovir (HPMPC) after intravitreal and intravenous administration in AIDS patients with cytomegalovirus retinitis. Cohort series; undiluted vitreous and blood were collected from 9 patients at the time of pars plana vitrectomy. Vitreous samples from 9 eyes of 9 patients and plasma samples from 4 patients were assayed with high-performance liquid chromatography to determine cidofovir levels. The only eye that had a detectable vitreous concentration (673.7 ng/ml) was injected with 20 microg 24 hours prior to the surgery. The remaining samples including plasma were below the detection point of the assay (100 ng/ml) and were injected between 5 and 40 days prior to sampling. The intravitreal concentration of cidofovir in humans is consistent with pharmacokinetics data in laboratory animals, and suggests that the long duration of antiviral effect (1-3 months) in clinical trials is due to a prolonged intracellular half-life in retinal tissue.

---

Metabolism / Metabolites
Cidofovir is converted via cellular enzymes to the pharmacologically active diphosphate metabolite ... .
This study was designed to evaluate the intraocular distribution and metabolism of the antiviral nucleotide analogs cidofovir and cyclic 1-[(S)-3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (HPMPC) in New Zealand white rabbits following intravitreal administration. ...Male rabbits received either 14C-cidofovir or 14C-cyclic HPMPC by intravitreal injection into both eyes (50 micrograms/eye, 11 microCi/eye). Two animals/group were sacrificed at 24, 48, 72 or 240 hr post-dose. Ocular tissues, kidney and liver were oxidized to determine total radioactivity and metabolites were determined by HPLC. ...At 24 hr post-dose, total radioactivity was 9.96 and 5.18 micrograms-equiv/g for cidofovir and cyclic HPMPC, respectively, in vitreous and 20.9 and 3.54 micrograms-equiv/g, respectively, in retina. Although the initial vitreal clearance was 2-fold faster for the cyclic analog, the estimated terminal elimination half-lives in vitreous (42 hr) and in retina (66-77 hr) were similar for both drugs. By 240 hr post-dose, radioactivity in all ocular tissues was approx ten-fold higher for cidofovir. Radioactivity in vitreous at 240 hr after intravitreal dosing with either drug contained cidofovir, cyclic HPMPC and cidofovir-phosphocholine. ...The long retinal half-life observed presumably reflects formation of phosphorylated cidofovir within retinal cells. Cidofovir achieved a ten-fold higher level of phosphorylated drug in retina than cyclic HPMPC. Therefore, intravitreal cidofovir may be expected to suppress progression of retinitis for a longer period than an equivalent intravitreal dose of cyclic HPMPC. The intravitreal half-life of cidofovir was 20-fold longer than that of ganciclovir in the same animal model.
Pyrimidine nucleoside monophosphate kinase converts cidofovir to cidofovir monophosphate, which is further converted to the diphosphate and cidofovir phosphate-choline via other cellular enzymes.

---

Biological Half-Life
2.4 to 3.2 hours
...Male rabbits received either 14C-cidofovir ...by intravitreal injection into both eyes (50 micrograms/eye...). ...The estimated terminal elimination half-lives /were/ in vitreous (42 hr) and in retina (66-77 hr)... .
...Levels of cidofovir in serum following iv infusion were dose proportional over the dose range of 1.0-10.0 mg/kg bw and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 hr (n=25).

---

After i.v. administration of 20 mg/kg to rats, Cidofovir showed a plasma half-life (t1/2) of 2.5 hours; volume of distribution (Vd) was 0.3 L/kg; 70% of the dose was excreted unchanged in urine within 24 hours [4]
- Low oral bioavailability (≈5%) in dogs; oral administration of 50 mg/kg resulted in peak plasma concentration (Cmax) of 0.8 μM, compared to 10 μM after i.v. dosing of the same amount [4]
- Plasma protein binding was <5% in human, rat, and dog plasma; no significant metabolism was observed in liver microsomes from multiple species [4]

Hepatotoxicity
Intravenous cidofovir therapy is associated with mild-to-moderate elevations in serum ALT levels in a proportion of patients, but the elevations are usually self-limited and do not require dose modification. Nephrotoxicity is often dose limiting, which may account for the absence of clinically significant cases of liver injury associated with cidofovir therapy. Cases of clinically apparent liver injury have been reported during cidofovir therapy, but the role of this agent has been difficult to define because most patients who receive cidofovir have severe immunodeficiency and are receiving multiple other agents, some of which are known hepatotoxins. Several instances of acute liver failure, lactic acidosis and fatty liver have been described in patients taking cidofovir, but other nucleoside analogues such as zidovudine, stavudine or didanosine were being taken concurrently.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of cidofovir during breastfeeding. The manufacturer recommends that breastfeeding be discontinued during cidofovir therapy. An alternate drug is preferred, especially while nursing a newborn or preterm infant.
◉ 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.

---

Protein Binding
6%

---

Interactions
Concomitant administration of cidofovir with potentially nephrotoxic agents (e.g., amphotericin B, aminoglycosides, foscarnet, nonsteriodal antiinflammatory agents, IV pentamidine, vancomycin) is contraindicated, and the manufacturer recommends that at least 7 days elapse between discontinuance of such drugs and administration of cidofovir.
Placement of a ganciclovir ocular implant in patients receiving IV cidofovir has resulted in profound hypotony in some patients, and some clinicians suggest that IV cidofovir not be administered within one month before or after placement of a ganciclovir ocular implant.

---

In rats, repeated i.v. administration of 40 mg/kg twice weekly for 4 weeks caused mild nephrotoxicity (increased serum creatinine and urea nitrogen); no other organ toxicity was detected [4]
- In dogs, the maximum tolerated dose (MTD) for i.v. administration was 30 mg/kg weekly; doses above 40 mg/kg resulted in severe nephrotoxicity and myelosuppression [4]
- Cytotoxicity in mammalian cells was low; CC50 > 100 μM in HFF, Vero, and HeLa cells; [1]

[1]. Antimicrob Agents Chemother . 1988 Dec;32(12):1839-44.

[2]. Antiviral Res . 1990 May;13(5):237-52.

[3]. Antiviral Res . 1992 Sep;19(3):181-92.

[4]. Antimicrob Agents Chemother . 1991 Apr;35(4):701-6.

[5]. Br J Dermatol . 2000 Oct;143(4):741-8.

Therapeutic Uses
Cidofovir is used for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).
Cidofovir has been used for the management of acyclovir-resistant herpes simplex virus (HSV-1 and HSV-2) infections in immunocompromised patients.
The role, if any, of cidofovir in the treatment of smallpox remains to be determined. Cidofovir is active in vitro against poxviruses, including variola virus (the causative agent of smallpox) and has in vivo activity in mice against cowpox and vaccinia virus. Although limited in vitro and in vivo data suggest that cidofovir might prove useful in preventing smallpox infection if administered within 1-2 days after exposure, there currently is no evidence that the antiviral would be more effective than vaccination in this early period.
Topical cidofovir gel eliminates virus shedding and lesions in some HIV-infected patients with acyclovir-resistant mucocutaneous HSV infections and has been use in treating anogenital warts and molluscum contagiosum in immunocompromised patients and cervical intraepithelial neoplasia in women. Intralesional cidofovir induces remission in adults or chlidren with respiratory papillomatosis.
For more Therapeutic Uses (Complete) data for CIDOFOVIR (15 total), please visit the HSDB record page.

---

Drug Warnings
Placement of a ganciclovir ocular implant in patients receiving IV cidofovir has resulted in profound hypotomy in some patients, and some clinicians suggest that IV cidofovir not be administered within one month before or after placement of a ganciclovir ocular implant.
.... Because evidence from clinical trials indicates that previous exposure to foscarnet may increase the risk of cidofovir-related nephrotoxicity, patients treated previously with foscarnet should receive cidofovir only when the potential benefits exceed the possible risks.
Patients should be advised that cidofovir therapy is not curative, and that progression of their retinitis is possible during or following therapy with the drug.
Safety and efficacy of cidofovir in geriatric patients older than 60 years of age have not been established. Because geriatric patients frequently have reduced glomerular filtration, particular attention should be paid to monitoring renal function prior to and during cidofovir therapy in this age group, and doses of the drug should be modified in response to changes in renal function that occur during therapy.
For more Drug Warnings (Complete) data for CIDOFOVIR (20 total), please visit the HSDB record page.

---

Pharmacodynamics
Cidofovir is a new anti-viral drug. It is classified as a nucleotide analogue and is active against herpes cytomegalovirus (CMV) retinitis infection. Most adults are infected with CMV. Cidofovir suppresses cytomegalovirus (CMV) replication by selective inhibition of viral DNA synthesis.

---

Cidofovir (GS 0504) is a nucleotide analog antiviral agent that requires phosphorylation to its active triphosphate form (cidofovir diphosphate) intracellularly [1]
- The active metabolite inhibits viral DNA polymerase by competing with dCTP and incorporating into viral DNA, leading to chain termination [3]
- Showed activity against antiviral-resistant strains of HCMV and HSV that are resistant to ganciclovir or acyclovir [2]
- Demonstrated potential for topical treatment of viral skin infections (e.g., HSV-induced lesions) due to low systemic absorption and local efficacy [5]

C8H14N3O6P

279.19

279.062

C, 34.42; H, 5.05; N, 15.05; O, 34.38; P, 11.09

113852-37-2

149394-66-1;142276-31-1

60613

White to off-white solid powder

1.8±0.1 g/cm3

609.5±65.0 °C at 760 mmHg

260ºC

322.4±34.3 °C

0.0±4.0 mmHg at 25°C

1.656

-3.37

157.71

4

6

6

18

417

1

OC[C@@H](OCP(O)(O)=O)CN1C=CC(N)=NC1=O

VWFCHDSQECPREK-LURJTMIESA-N

InChI=1S/C8H14N3O6P/c9-7-1-2-11(8(13)10-7)3-6(4-12)17-5-18(14,15)16/h1-2,6,12H,3-5H2,(H2,9,10,13)(H2,14,15,16)/t6-/m0/s1

[(2S)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethylphosphonic acid

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)

配方 1 中的溶解度: 4.55 mg/mL (16.30 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).

---

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。