Cell viability is lowered by aciclovir sodium (3-100 µM; 24-72 hours; Jurkat, U937, and K562 leukemia cells) in a way that is dependent on both dose and time [1]. Aciclovir sodium (10-100 µM; 24-72 hours; Jurkat cells) raises the sub-G1 hypodiploid peak and inhibits DNA synthesis, stopping the cell cycle in the G2/M and S phases. 1]. Aciclovir sodium (10-100 µM; 24-72 hours; Jurkat cells) activates caspase-3 and fragments nuclear DNA to cause apoptosis [1].

Aciclovir sodium (20 mg/kg; oral; three times daily; 10 days) prevents skin lesions from forming and separates the formation of antibodies from DTH reactions. [3]

Cell Viability Assay[1]
Cell Types: Jurkat, U937 and K562 Leukemia cell
Tested Concentrations: 3, 10, 30 and 100 µM
Incubation Duration: 24, 48 and 72 hrs (hours)
Experimental Results: demonstrated a dose and time dependent decrease in cell viability.

---

Apoptosis analysis[1]
Cell Types: Jurkat Cell
Tested Concentrations: 10 and 100 µM
Incubation Duration: 24, 48 and 72 hrs (hours)
Experimental Results: Increased caspase-3 activity and cleavage of internucleosomal DNA.

---

Cell cycle analysis[1]
Cell Types: Jurkat cells
Tested Concentrations: 10 and 100 µM
Incubation Duration: 24, 48 and 72 hrs (hours)
Experimental Results: Dose-dependent accumulation of cells in S phase after 24 and 48 hrs (hours). After 72 hrs (hours), there was a dose-dependent increase in the sub-G1 hypodiploid peak.

Animal/Disease Models: Specific - Pathogen-free balb/c (Bagg ALBino) mouse (7 weeks old) infected with HSV-1 [3]
Doses: 20 mg/kg
Route of Administration: po (po (oral gavage)) three times daily; for 10 days
Experimental Results: Inhibition of skin The lesions develop and result in a dissociation between the DTH response and antibody production.

Absorption, Distribution and Excretion
The oral bioavailability of acyclovir is 10-20% but decreases with increasing doses. Acyclovir ointment is <0.02-9.4% absorbed. Acyclovir buccal tablets and ophthalmic ointment are minimally absorbed. The bioavailability of acyclovir is not affected by food. Acyclovir has a mean Tmax of 1.1±0.4 hours, mean Cmax of 593.7-656.5ng/mL, and mean AUC of 2956.6-3102.5h/*ng/mL.
The majority of acyclovir is excreted in the urine as unchanged drug. 90-92% of the drug can be excreted unchanged through glomerular filtration and tubular secretion. <2% of the drug is recovered in feces and <0.1% is expired as CO₂.
The volume of distribution of acyclovir is 0.6L/kg.
The renal clearance of acyclovir is 248mL/min/1.73m². The total clearance in neonates if 105-122mL/min/1.73m².
Absorption of acyclovir from the GI tract is variable and incomplete. 15-30% of an oral dose of the drug is absorbed. Some data suggest that GI absorption of acyclovir may be saturable; in a crossover study in which acyclovir was administered orally to healthy adults as 200 mg capsules, 400 mg tablets, or 800 mg tablets 6 times daily, the extent of absorption decreased with increasing dose, resulting in bioavailabilities of 20, 15, or 10%, respectively. ... This decrease in bioavailability appears to be a function of increasing dose, not differences in dosage forms. In addition, steady-state peak and trough plasma acyclovir concentrations were not dose proportional over the oral dosing range of 200-800 mg 6 times daily, averaging 0.83 and 0.46, 1.21 and 0.63, or 1.61 and 0.83 ug/ml for the 200, 400, or 800 mg dosing regimens, respectively. Peak plasma concentrations usually occur within 1.5-2.5 hours after oral administration.
In a multiple dose study in neonates up to 3 months of age, IV infusion over 1 hour of 5, 10, or 15 mg/kg of acyclovir every 8 hours resulted in mean steady state peak serum concentrations of 6.8, 13.9, and 19.6 ug/ml, respectively, and mean steady state trough serum concentration of 1.2, 2.3, and 3.1 ug/ml, respectively. In another multiple dose study in pediatric patients, IV infusion over 1 hour of 250 or 500 mg/sq m of acyclovir every 8 hours resulted in mean steady state peak serum concentrations of 10.3 and 20.7 ug/ml, respectively.
Acyclovir is widely distributed into body tissues and fluids including the brain, kidney, saliva, lung, liver, muscle, spleen, uterus, vaginal mucosa and secretions, cerebrospinal fluid, and herpetic vesicular fluid. The drug also is distributed into semen, achieving concentrations about 1.4 and 4 times those in plasma during chronic oral therapy at dosages of 400 mg and 1 g daily, respectively. The apparent volume of distribution of acyclovir is reported to be 32.4-61.8 liter/1.73 sq m in adults and 28.8, 31.6, 42, or 51.2-53.6 liter/1.73 sq m in neonates up to 3 months of age, children 1-2 years; 2-7 years; or 7-12 years of age, respectively.
Acyclovir crosses the placenta. Limited data indicate that the drug is distributed into milk, generally in concentrations greater than concurrent maternal plasma concentrations, possibly via an active transport mechanism.
For more Absorption, Distribution and Excretion (Complete) data for ACYCLOVIR (13 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Acyclovir is <15% oxidized to 9-carboxymethoxymethylguanine by alcohol dehydrogenase and aldehyde dehydrogenase and 1% 8-hydroxylated to 8-hydroxy-acyclovir by aldehyde oxidase. Acyclovir is becomes acyclovir monophosphate due to the action of viral thymidine kinase. Acyclovir monophosphate is converted to the diphosphate form by guanylate kinase. Acyclovir diphosphate is converted to acyclovir triphosphate by nucleoside diphosphate kinase, pyruvate kinase, creatine kinase, phosphoglycerate kinase, succinyl-CoA synthetase, phosphoenolpyruvate carboxykinase and adenylosuccinate synthetase.
Acyclovir is metabolized partially to 9-carboxymethoxymethylguanine and minimally to 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine. In vitro, acyclovir also is metabolized to acyclovir monophosphate, diphosphate, and triphosphate in cells infected with herpes viruses, principally by intracellular phosphorylation of the drug by virus coded thymidine kinase and several cellular enzymes.

---

Biological Half-Life
The clearance of acyclovir varies from 2.5-3 hours depending on the creatinine clearance of the patient. The plasma half life of acyclovir during hemodialysis is approximately 5 hours. The mean half life in patients from 7 months to 7 years old is 2.6 hours.
Plasma concentrations of acyclovir appear to decline in a biphasic manner. In adults with normal renal function, the half-life of acyclovir in the initial phase averages 0.34 hours and the half-life in the terminal phase averages 2.1-3.5 hours. In adults with renal impairment, both half-life in the initial phase and half-life in the terminal phase may be prolonged, depending on the degree of renal impairment. In a study in adults with anuria, the half-life in the initial phase of acyclovir averaged 0.71 hours. In several studies, the half-life in the terminal phase of acyclovir averaged 3,3.5, or 19.5 hours in adults with creatinine clearances of 50-80 or 15-50 ml/minute per 1.73 sq m or with anuria, respectively. In patients undergoing hemodialysis, the half-life in the terminal phase of acyclovir during hemodialysis averaged 5.4-5.7 hours.
In neonates, the half-life of acyclovir depends principally on the maturity of renal mechanisms for excretion as determined by gestational age, chronologic age, and weight. In children older than 1 year of age, the half-life of the drug appears to be similar to that of adults. The half-life in the terminal phase averages 3.8-4.1, 1.9, 2.2-2.9, or 3.6 hours in neonates up to 3 months of age, children 1-2 years, 2-12 years, or 12-17 years of age, respectively.

Hepatotoxicity
Despite widespread use, there is little evidence that acyclovir when given orally causes significant liver injury. Serum enzyme levels generally do not change during oral acyclovir therapy. High dose intravenous administration of acyclovir is associated with renal dysfunction and thrombocytopenia, and occasionally with transient mild-to-moderate elevations in serum ALT levels, which have been asymptomatic and self-limited. There have rare instances of acute, clinically apparent liver injury reported that were attributed to acyclovir or valacyclovir (a prodrug of acyclovir with better oral absorption), but these have not been particularly convincing. Some degree of liver injury and even jaundice can occur during the course of herpes simplex or varicella zoster infection, and these complications could be mistaken for drug induced liver injury. Furthermore, in the reported cases, patients were receiving other medications and had other unlying comorbidities that may have been responsible for the liver injury.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Even with the highest maternal dosages, the dosage of acyclovir in milk is only about 1% of a typical infant dosage and would not be expected to cause any adverse effects in breastfed infants. Topical acyclovir applied to small areas of the mother's body away from the breast should pose no risk to the infant. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking.[1]
◉ Effects in Breastfed Infants
The mother of a 4-month-old infant noticed no adverse effects in her breastfed infant while she was taking an acyclovir dosage of 800 mg orally 5 times daily.[5]
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
Acyclovir is 9-33% protein bound in plasma.

---

Interactions
Acyclovir has been used concomitantly with zidovudine ... without evidence of increased toxicity; however, neurotoxicity (profound drowsiness and lethargy), which recurred on rechallenge, has been reported in at least one patient with acquired immunodeficiency syndrome (AIDS) during concomitant therapy with the drugs. Neurotoxicity was evident within 30-60 days after initiation of IV acyclovir therapy, persisted with some improvement when acyclovir was administered orally, and resolved following discontinuance of acyclovir in this patient.
This study reports the effects of a combination of azidothymidine plus acyclovir on both pluripotent (spleen colony forming units) and committed (granulocyte-macrophage colony forming units; erythroid burst forming units) murine hemopoietic progenitors. Administration of azidothymidine alone was associated with severe hematotoxicity, as shown by the marked decrease of all the hemopoietic progenitor populations tested, that is, spleen colony forming units, granulocyte-macrophage colony forming units, and erythroid burst forming units. This, however, was followed by a prompt recovery of hemopoiesis. Administration of acyclovir alone did not modify the hematological parameters studied, whereas the combined administration of azidothymidine and acyclovir led to changes in peripheral blood cells and bone marrow hemopoietic progenitors that were, on the whole, not significantly different from those observed with azidothymidine alone. Only the decrease in spleen colony forming units was significantly more severe, but their recovery was as rapid as that of the committed progenitors. Thus, in this experimental setting, the addition of acyclovir to azidothymidine does not appear to increase the hematotoxicity of the latter.
The combined effect of acyclovir and chlorhexidine on the replication and DNA synthesis of herpes simplex virus was studied. Acyclovir and chlorhexidine showed synergism in the inhibition of the viral replication by enhancing in part the reduction of viral DNA synthesis. These data indicate that combined therapy with acyclovir and chlorhexidine might be beneficial for the control of intraoral herpetic infections.
Acyclovir may decrease the renal clearance of other drugs eliminated by active renal secretion, such as methotrexate.
For more Interactions (Complete) data for ACYCLOVIR (6 total), please visit the HSDB record page.

---

Non-Human Toxicity Values
LD50 Mouse oral > 10,000 mg/kg
LD50 Mouse ip 1000 mg/kg

[1]. Acyclovir induces cell cycle perturbation and apoptosis in Jurkat leukemia cells, and enhances chemotherapeutic drug cytotoxicity. Life Sci. 2018 Dec 15;215:80-85.

[2]. Synergistic antiviral activity of acyclovir and vidarabine against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antiviral Res. 2006 Nov;72(2):157-61.

[3]. Acyclovir treatment of skin lesions results in immune deviation in mice infected cutaneously with herpes simplex virus. Antivir Chem Chemother. 1999 Sep;10(5):251-7.

[4]. Oral acyclovir as prophylaxis for bacterial infections during induction therapy for acute leukaemia in adults. The Leukemia Group of Middle Sweden. Support Care Cancer. 1993 May;1(3):139-44.

Therapeutic Uses
Antiviral Agents
IV acyclovir sodium is used for the treatment of initial and recurrent mucocutaneous herpes simplex virus (HSV-1 and HSV-2) infections and the treatment of varicella-zoster infections in immunocompromised adults and children; for the treatment of severe first episodes of genital herpes infections in immunocompetent individuals; and for the treatment of HSV encephalitis and neonatal HSV infections.
Acyclovir is used orally for the treatment of initial and recurrent episodes of genital herpes; for the acute treatment of herpes zoster (shingles, zoster) in immunocompetent individuals; and for the treatment of varicella (chickenpox) in immunocompetent individuals.
Oral acyclovir is indicated in the treatment of initial episodes of genital herpes infection in immunocompetent and immunocompromised patients. Parenteral acyclovir is indicated in the treatment of severe initial episodes of genital herpes infection in immunocompetent patients and in patients who are unable to take (or absorb) oral acyclovir. /Included in US product labeling/
For more Therapeutic Uses (Complete) data for ACYCLOVIR (15 total), please visit the HSDB record page.

---

Drug Warnings
Parenteral acyclovir therapy can cause signs and symptoms of encephalopathy. ... Acyclovir should be used with caution in patients with underlying neurologic abnormalities and in patients with serious renal, hepatic, or electrolyte abnormalities or substantial hypoxia. The drug also should be used with caution in patients who have manifested prior neurologic reactions to cytotoxic drugs or those receiving intrathecal methotrexate or interferon.
Acyclovir should be used with caution in patients receiving other nephrotoxic drugs concurrently since the risk of acyclovir-induced renal impairment and/or reversible CNS symptoms is increased in these patients. Adequate hydration should be maintained in patients receiving IV acyclovir; however, in patients with encephalitis, the recommended hydration should be balanced by the risk of cerebral edema. Because the risk of acyclovir-induced renal impairment is increased during rapid IV administration of the drug, acyclovir should be given only by slow IV infusion (over 1 hour).
There are no adequate and controlled studies to date using acyclovir in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
Maternal Medication usually Compatible with Breast-Feeding: Acyclovir: Reported Sign or Symptom in Infant or Effect on Lactation: None. /from Table 6/
For more Drug Warnings (Complete) data for ACYCLOVIR (20 total), please visit the HSDB record page.

---

Pharmacodynamics
Acyclovir is a nucleoside analog that inhibits the action of viral DNA polymerase and DNA replication of different herpesvirus. Acyclovir has a wide therapeutic window as overdose is rare in otherwise healthy patients.

C8H10N5NAO3

247.18

247.068

69657-51-8

Acyclovir;59277-89-3;Acyclovir alaninate;84499-64-9

135398513

Crystals from methanol
Crystals from ethanol
White, crystalline powder

613.1ºC at 760 mmHg

0.099

3

5

4

16

308

0

C1=NC2=C([N]1COCCO)N=C(N=C2[O-])N.[Na+]

MKUXAQIIEYXACX-UHFFFAOYSA-N

InChI=1S/C8H11N5O3/c9-8-11-6-5(7(15)12-8)10-3-13(6)4-16-2-1-14/h3,14H,1-2,4H2,(H3,9,11,12,15)

2-amino-9-(2-hydroxyethoxymethyl)-1H-purin-6-one

Aciclovir sodiumAcyclovir sodium

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

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 Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

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
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

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