Penciclovir

Penciclovir is an inhibitor of HSV-1 DNA synthesis [1].

Penciclovir is a guanine derivative and is used as a drug for the treatment against herpesviruses. Penciclovir has a similar spectrum of activity with acyclovir. In the plaque reduction assay, penciclovir shows potent inhibitory activities against HSV-1, HSV-2 and VZV with IC50 values of 0.4μg/ml, 1.5μg/ml and 3.1μg/ml, respectively. It also shows minimal activity against CMV. In MRC-5 cells, penciclovir inhibits the replication of HSV-1 with IC99 value of 0.4μg/ml. Moreover, penciclovir exerts persistent antiviral activity against HSV-1and HSV-2 in Vero cells. Besides that, penciclovir is found to be phosphorylated to the triphosphate in HSV-1-infected MRC-5 cells. The penciclovir triphosphate is the metabolite that actually inhibits herpesvirus replication. Penciclovir inhibits HSV-1 DNA synthesis with IC50 value of 0.16μM without effect on cellular DNA synthesis [1, 2].

References:
[1] Boyd M R, Bacon T H, Sutton D, et al. Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl) guanine (BRL 39123) in cell culture. Antimicrobial agents and chemotherapy, 1987, 31(8): 1238-1242.
[2] Hodge R A, Perkins R M. Mode of action of 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine (BRL 39123) against herpes simplex virus in MRC-5 cells. Antimicrobial agents and chemotherapy, 1989, 33(2): 223-229.

Pharmacokinetic modeling of penciclovir and BRL42359 in the plasma and tears of healthy cats to optimize dosage recommendations for oral administration of famciclovir.[Pubmed:27463546]

Am J Vet Res. 2016 Aug;77(8):833-45.

OBJECTIVES To determine, following oral administration of famciclovir, pharmacokinetic (PK) parameters for 2 of its metabolites (Penciclovir and BRL42359) in plasma and tears of healthy cats so that famciclovir dosage recommendations for the treatment of herpetic disease can be optimized. ANIMALS 7 male domestic shorthair cats. PROCEDURES In a crossover study, each of 3 doses of famciclovir (30, 40, or 90 mg/kg) was administered every 8 or 12 hours for 3 days. Six cats were randomly assigned to each dosage regimen. Plasma and tear samples were obtained at predetermined times after famciclovir administration. Pharmacokinetic parameters were determined for BRL42359 and Penciclovir by compartmental and noncompartmental methods. Pharmacokinetic-pharmacodynamic (PK-PD) indices were determined for Penciclovir and compared among all dosage regimens. RESULTS Compared with Penciclovir concentrations, BRL42359 concentrations were 5- to 11-fold greater in plasma and 4- to 7-fold greater in tears. Pharmacokinetic parameters and PK-PD indices for the 90 mg/kg regimens were superior to those for the 30 and 40 mg/kg regimens, regardless of dosing frequency. Penciclovir concentrations in tears ranged from 18% to 25% of those in plasma. Administration of 30 or 40 mg/kg every 8 hours achieved Penciclovir concentrations likely to be therapeutic in plasma but not in tears. Penciclovir concentrations likely to be therapeutic in tears were achieved only with the two 90 mg/kg regimens. CONCLUSIONS AND CLINICAL RELEVANCE In cats, famciclovir absorption is variable and its metabolism saturable. Conversion of BRL42359 to Penciclovir is rate limiting. The recommended dosage of famciclovir is 90 mg/kg every 12 hours for cats infected with feline herpesvirus.

Controlled release delivery of penciclovir via a silicone (MED-4750) polymer: kinetics of drug delivery and efficacy in preventing primary feline herpesvirus infection in culture.[Pubmed:24558980]

Virol J. 2014 Feb 22;11:34.

BACKGROUND: Herpesviruses are ubiquitous pathogens that infect and cause recurrent disease in multiple animal species. Feline herpesvirus-1 (FHV-1), a member of the alphaherpesvirus family, causes respiratory illness and conjunctivitis, and approximately 80% of domestic cats are latently infected. Oral administration of famciclovir or topical application of cidofovir has been shown in masked, placebo-controlled prospective trials to reduce clinical signs and viral shedding in experimentally inoculated cats. However, to the authors' knowledge, other drugs have not been similarly assessed or were not safe or effective. Likewise, to our knowledge, no drugs have been assessed in a placebo-controlled manner in cats with recrudescent herpetic disease. Controlled-release devices would permit long-term administration of these drugs and enhance compliance. METHODS: We therefore engineered implantable cylindrical devices made from silicone (MED-4750) impregnated with Penciclovir, for long-term, steady-state delivery of this drug. RESULTS: Our data show that these devices release Penciclovir with a burst of drug delivery until the tenth day of release, then at an average rate of 5.063 +/- 1.704 mug per day through the next 50 days with near zero-order kinetics (in comparison to MED-4750-acyclovir devices, which show the same burst kinetics and average 2.236 +/- 0.625 mug/day thereafter). Furthermore, these devices suppress primary infection of FHV-1 in a cell culture system. CONCLUSIONS: The clinical deployment of these silicone-Penciclovir devices may allow long-term treatment of FHV-1 infection with a single intervention that could last the life of the host cat.

(3)H-Penciclovir ((3)H-PCV) Uptake Assay.[Pubmed:27446976]

Bio Protoc. 2013 Sep 5;3(17).

Thymidine Kinase from human Herpes simplex virus type 1 (HSV1-TK) in combination with specific substrate prodrug nucleotide analogue ganciclovir (GCV) has been widely used as suicidal therapeutic gene for cancer gene therapy. HSV1, and its mutant (HSV1-sr39TK) with improved substrate specificity, were used as reporter genes for PET-imaging of various biological functions in small animals, by combining with radiolabeled substrates such as (18)F-FHBG and (124)I-FIAU. (3)H-Penciclovir (PCV) uptake assay is a method of choice used to determine the expression level of HSV1-TK in mammalian cells and tissues. HSV1-TK phosphorylate PCV and result in the formation of Penciclovir monophosphate, and its subsequent phopsphorylation by cellular TK lead to the formation of Penciclovir triphosphate, which is trapped selectively in cells expressing HSV-TK. (3)H-Penciclovir enables the detection of Penciclovir uptake of mammalian cells and tissues by radioactive procedures such as scintillation counting. Here we describe the protocol to carry out (3)H-Penciclovir uptakes in mammalian cells.

Indirect photochemical transformations of acyclovir and penciclovir in aquatic environments increase ecological risk.[Pubmed:26356329]

Environ Toxicol Chem. 2016 Mar;35(3):584-92.

Acyclovir and Penciclovir, 2 antiviral drugs, are increasingly detected in aquatic environments. The present study explores the natural photochemical transformation mechanisms and fate of these drugs, examining direct and indirect photochemical transformation under simulated sunlight irradiation. The 2 antiviral drugs are photostable under certain conditions but significantly degrade in the presence of chromophoric dissolved organic matter (DOM). The degradation rate associated with the drugs' indirect photochemical transformation scaled with chromophoric DOM concentration. Quenchers and sensitizers were used to identify indirect photochemical transformation mechanism. Results suggested that both pharmaceuticals could be transformed by reacting with (1)O2, (*)OH, and excited chromophoric DOM. The (1)O2 played an important role in indirect photochemical transformation. Furthermore, the reaction kinetics between their substructural molecules, guanine, isocytosine, and imidazole, with different reactive oxygen species were evaluated to determine which substrate functionalities were most susceptible to singlet oxygenation. Imidazole was identified as the reaction site for (1)O2, and preliminary (1)O2 oxidation mechanisms were further evaluated based on liquid chromatographic-tandem mass spectrometric results. Finally, aquatic ecotoxicity assessment of phototransformed solutions revealed that the degradation of acyclovir and Penciclovir may not ultimately diminish environmental risk because of either formation of more toxic intermediates than parent pharmaceuticals or some synergistic effects existing between the intermediates.