HSV-1(EC50=0.5 μg/mL);HSV-2(EC50=0.8 μg/mL)

With EC50s of 0.5, 0.8, 2.4, 52, 100, 1.2, 1.6, 0.9, >100 µg/ml for HSV-1 (HFEM), HSV-2 (MS), VZV (Ellen), CMV (AD-169), BHV-1 (Oxford 1964), BHV-2 (New York 1), EHV-1 (Quai Hals), FHV-1 (B927), and SVV, respectively, penciclovir (0-100 µg/ml) exhibits anti-herpesvirus activity.To human cells that are not infected, penciclovir (0-100 µg/ml) exhibits no toxicity[1].

Penciclovir (100 mg/kg; s.c.; daily for 5 days) preventes mortality in mouse[2].

Human breast cancer cell lines MCF-7 and MDA-MB-435, glioblastoma U87MG, and embryonic kidney cells 293T are cultured at 37°C in a humidified atmosphere containing 5% CO2 in Iscove’s modified Dulbecco medium or Leibovitz’s L-medium and 5% fetal bovine serum (FBS). The assays are performed with slight modifications. In brief, cells are seeded into 24-well plates (5×104 cells/well) and infected 48 h later with 103 particles per cell of unmodified virus (Adtk), PEGylated virus (PEG-Adtk), or RGD-PEG-modified virus (RGD-PEG-Adtk) in triplicates in culture medium with 2% FBS and incubated for 4 h at 37°C. The incubation medium is then replaced by normal medium and cells are further incubated for 48 h. Cells are harvested and lysed with 500 μL of TK lysis buffer that contained 0.5% Nonidet P-40 (NP-40), 20 mM N-(2-hydroxyethyl) piperazine-N′-(2-ethanesulfonic acid) (HEPES) (pH 7.6), 2 mM Mg(OAc)2, 1 mM dithiothreitol, and 50 μM thymidine. The supernatant is collected after centrifugation. The samples are kept at -80°C until use. The modified and unmodified adenovirus protein concentrations are determined by the Micro BCA assay. One microgram of cell extract is incubated with HSV1-tk substrate 8-3H-Penciclovir (8-3 H-PCV). The phosphorylated tracer is separated from unphosphorylated 8-3 H-PCV with DE-81 filters. TK activity is expressed as the percentage of conversion of substrate per minute per microgram protein.

Animal Model: Three-week-old female Balb/c mice[2]
Dosage: 100 mg/kg
Administration: S.c.; daily for 5 days
Result: decreased viral titres in the respiratory systems of mice infected with PR3 and W/t.

Absorption, Distribution and Excretion
In healthy male volunteers (n=12), no measurable concentrations of penciclovir were detected in plasma or urine following single or repeated administration of the 1% cream (180 mg penciclovir daily dose, approximately 67 times the estimated usual clinical dose). There is currently no information regarding whether penciclovir is excreted into human breast milk after topical application. However, in lactating rats, after oral administration of famciclovir (an oral prodrug of penciclovir), penciclovir concentrations in breast milk were higher than in plasma. This study investigated the pharmacokinetics of the novel antiherpes drug penciclovir (BRL 39,123A) via intravenous injection in 15 healthy male subjects. Volunteers were divided into three groups and received penciclovir at doses of 10, 15, or 20 mg/kg, administered via a constant infusion rate over 60 minutes. Blood samples were collected continuously for 48 hours after the start of infusion, and urine samples were collected at appropriate time intervals until 72 hours. Plasma and urine concentrations of penciclovir were determined using high-performance liquid chromatography-ultraviolet detection after simple solid-phase extraction. The mean Cmax (usually corresponding to the end of the infusion) and AUC appeared to increase proportionally with the dose. Furthermore, there was no evidence that the dose significantly affected any single pharmacokinetic parameter. Penciclovir is distributed in tissues with a total mean volume of distribution of approximately 1.5 L·kg⁻¹, approximately twice that of body fluids. It is rapidly eliminated, with a mean total plasma clearance of 39.3 L·hr⁻¹ and a mean terminal half-life of 2.0 hours. Approximately 70% of the dose is excreted unchanged in the urine. The mean renal clearance of BRL 39,123 was 28.1 L·hr⁻¹, exceeding normal glomerular filtration rate and approaching renal plasma flow. Following a single oral dose of 500 mg of radiolabeled famciclovir in three healthy male volunteers, 73% and 27% of the administered radioactive material were recovered in urine and feces, respectively, within 72 hours. Penciclovir accounted for 82% of the radioactive material excreted in urine, and 6-deoxypenciclovir accounted for 7%. Approximately 60% of the radiolabeled dose was excreted in urine within the first 6 hours after administration. For more complete data on absorption, distribution, and excretion of penciclovir (15 items), please visit the HSDB record page. Metabolism/Metabolites Hepatic Metabolism Following oral administration, famciclovir is deacetylated and oxidized to penciclovir. Inactive metabolites include 6-deoxypenciclovir, monoacetylated penciclovir, and 6-deoxymonoacetylated penciclovir (5%, <0.5%, and <0.5% of the urinary dose, respectively). Famciclovir is barely detectable in plasma or urine. An in vitro study using human liver microsomes indicated that cytochrome P450 does not play a significant role in famciclovir metabolism. The conversion of 6-deoxypenciclovir to penciclovir is catalyzed by aldehyde oxidase. Famciclovir is deacetylated and oxidized to penciclovir. In cells infected with HSV-1, HSV-2, or VZV, penciclovir is phosphorylated to penciclovir triphosphate (the active metabolite). The inactive metabolite 6-deoxypenciclovir is converted to penciclovir by aldehyde oxidase. Famciclovir is not metabolized by CYP enzymes.

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Biological Half-Life
2 hours
After oral administration of famciclovir, the elimination half-life of penciclovir is 1.6–3 hours. In cells infected with herpes simplex virus (HSV)-1 or HSV-2, the intracellular half-life of penciclovir triphosphate is 10 hours and 20 hours, respectively; in cells infected with varicella-zoster virus (VZV), the intracellular half-life is 7–14 hours.
The pharmacokinetics of the novel antiherpes drug penciclovir (BRL 39,123A) administered intravenously were studied in 15 healthy male subjects. The mean terminal half-life was reported to be 2.0 hours. In 48 healthy male volunteers, the plasma elimination half-life after intravenous penciclovir was 2.0 ± 0.3 hours; in 124 healthy male volunteers, the plasma elimination half-life after oral administration of 500 mg famciclovir was 2.3 ± 0.4 hours. The half-lives in 17 patients with herpes zoster were 2.8 ± 1.0 hours after a single dose and 2.7 ± 1.0 hours after repeated doses, respectively.

Effects During Pregnancy and Lactation
◉ Overview of use during lactation While there is currently no literature on the use of penciclovir during lactation, it is unlikely that infant side effects will occur if the mother applies it topically to a small area of skin away from the breast. Only water-soluble creams or gels should be applied to the breast, as ointments may expose the infant to high concentrations of mineral oil through licking. [1] ◉ Effects on breastfed infants No published information was found as of the revision date. ◉ Effects on lactation and breast milk No published information was found as of the revision date. Protein binding is less than 20%.

[1]. Penciclovir: a review of its spectrum of activity, selectivity, and cross-resistance pattern. Antiviral Chemistry and Chemotherapy, 1993, (1): 3-11.

[2]. The acyclic nucleoside analogue penciclovir is a potent inhibitor of equine herpesvirus type 1 (EHV-1) in tissue culture and in a murine model. Antiviral Res. 1992 May;18(1):77-89.

Therapeutic Uses

Antiviral drug; Reverse transcriptase inhibitor
Denavir (penciclovir cream) is indicated for the treatment of recurrent cold sores (herpes labialis) in adults and children 12 years of age and older. /US product label contains/
Drug Warnings

Denavir is intended for use on the lips and face only. Due to a lack of data, it is not recommended for use on human mucous membranes. Special care should be taken to avoid application to or around the eyes, as it may cause irritation. Lesions that do not improve or worsen after treatment should be evaluated for secondary bacterial infection. The efficacy of Denavir in immunocompromised patients has not been established.
FDA Pregnancy Risk Category: B / No evidence of risk in humans. Although adverse reactions have been observed in animal studies, adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal malformations; or, in the absence of adequate human studies, animal studies have shown no fetal risk. The possibility of fetal harm is small but still exists. There is currently no information regarding whether penciclovir is excreted into human breast milk after topical application. However, after oral administration of famciclovir (an oral prodrug of penciclovir) to lactating rats, the concentration of penciclovir in breast milk was higher than that in plasma. Therefore, the importance of the drug to the mother should be considered when deciding whether to discontinue the drug. In 74 patients aged ≥65 years, the adverse event profile was similar to that observed in younger patients. For more complete data on penciclovir (9 of 9), please visit the HSDB record page.

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Pharmacodynamics
Penciclovir is the active metabolite of the oral drug famciclovir. Topical penciclovir is more effective in treating cold sores than topical acyclovir, likely due to its longer intracellular half-life within HSV-infected cells. The activated drug inhibits viral DNA polymerase, thereby weakening the virus's ability to replicate intracellularly.

C10H15N5O3

253.26

253.117

C, 47.42; H, 5.97; N, 27.65; O, 18.95

39809-25-1

Penciclovir-d4;1020719-72-5;Penciclovir sodium;97845-62-0

135398748

White crystalline solid from water (monohydrate) ... also reported as colorless matted needles

1.7±0.1 g/cm3

636.7±65.0 °C at 760 mmHg

275-277°C

338.9±34.3 °C

0.0±2.0 mmHg at 25°C

1.749

-3.58

4

5

5

18

344

0

O([H])C([H])([H])C([H])(C([H])([H])O[H])C([H])([H])C([H])([H])N1C([H])=NC2C(N([H])C(N([H])[H])=NC1=2)=O

JNTOCHDNEULJHD-UHFFFAOYSA-N

InChI=1S/C10H15N5O3/c11-10-13-8-7(9(18)14-10)12-5-15(8)2-1-6(3-16)4-17/h5-6,16-17H,1-4H2,(H3,11,13,14,18)

2-amino-9-[4-hydroxy-3-(hydroxymethyl)butyl]-3H-purin-6-one

BRL-39123; BRL 39123; BRL39123; VSA 671; VSA671; VSA-671; Penciclovir; Denavir, Vectavir and Fenivir.

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 : 25~34 mg/mL (98.71~134.24 mM)
H2O : ~2 mg/mL (~7.90 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.87 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 (9.87 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 (9.87 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: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (9.87 mM)

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