Ganciclovir
Synonym(s):Ganciclovir;GNC;2-Amino-1,9-dihydro-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one;9-(1,3-Dihydroxy-2-propoxymethyl)guanine;9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine
- CAS NO.:82410-32-0
- Empirical Formula: C9H13N5O4
- Molecular Weight: 255.23
- MDL number: MFCD00870588
- EINECS: 627-054-3
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-19 20:33:22
What is Ganciclovir?
Absorption
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).
Toxicity
Oral, mouse LD50: > 2g/kg. Intravenous, dog LD50: > 150mg/kg. Symptoms of overdose include irreversible pancytopenia, worsening GI symptoms, and acute renal failure. Suspected cancer agent.
Description
Ganciclovir is a parenterally-active antiviral agent indicated for sight- or life-threatening cytomegalovirus (CMV) infections in immunocompromised patients. Its suppressive effects on bone marrow and renal tubular secretion/absorption are reported to present potential limitations on adjunct therapies involving zidovudine, vincristine, adriamycin and amphotericin B. Recently, the emergence of CMV strains resistant to ganciclovir therapy has been reported.
Description
Ganciclovir is a synthetic analog of 2''-
Chemical properties
White Powder
Originator
Enscor (United Kingdom)
The Uses of Ganciclovir
antiemetic
The Uses of Ganciclovir
Ganciclovir is a nucleoside analog structurally related to Acyclovir (A192400). Ganciclovir is an antiviral.
The Uses of Ganciclovir
Ganciclovir may be used as a pharmaceutical reference standard for the determination of the analyte in pharmaceutical formulations by chromatography techniques.
What are the applications of Application
Ganciclovir is A nucleoside analog structurally related to Acyclovir
Indications
For induction and maintenance in the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). Also used in the treatment of severe cytomegalovirus (CMV) disease, including CMV pneumonia, CMV gastrointestinal disease, and disseminated CMV infections, in immunocompromised patients.
Background
An acyclovir analog that is a potent inhibitor of the Herpesvirus family including cytomegalovirus. Ganciclovir is used to treat complications from AIDS-associated cytomegalovirus infections.
Definition
ChEBI: An oxopurine that is guanine substituted by a [(1,3-dihydroxypropan-2-yl)oxy]methyl group at position 9. Ganciclovir is an antiviral drug used to treat or prevent AIDS-related cytomegalovirus infections.
Indications
Ganciclovir (Cytovene) is an acyclic analogue of 2 deoxyguanosine with inhibitory activity toward all herpesviruses, especially CMV.
Manufacturing Process
Sodium hydride (100 g (50% dispersion in mineral oil), 2.08 mol) was washed
twice with 1 L of hexane then dried under nitrogen. Dry DMF (1.5 L) was
added. Benzyl alcohol (400 ml) was then added at for 2 hours such a rate to
keep the temperature below 50°C. Epichlorohydrin (92.5 g, 1 mol) was then
added dropwise over 0.5 hour with ice cooling in order to keep the
temperature below 40°C. The solution was next stirred for 16 hours at 21°C
then for 2.5 hours at 50°C. DMF was then removed by evaporation at reduced
pressure. The oily residue was dissolved in 2.5 L diethyl ether. The organic
solution was washed with 2 L of water, 2 L of 2% hydrochloric acid, 2 L of 1%
sodium bicarbonate, and 1 L of brine, dried over sodium sulfate, and
concentrated to a brown oil. Distillation gave 147.8 g of 1,3-di-Obenzylglycerol (boiling point 170-180°C/1 torr).
Dry hydrogen chloride gas was bubbled for 1.5 hours into a solution of 1,3-diO-benzylglycerol (15 g, 55 mmole) and paraformaldehyde (3.3 g, 110 mmol)
in 175 ml of 1,2-dichloroethane at 0°C. The solution was then stored in a
stoppered flask for 21 hours at 4°C. Next, the solution was dried over
magnesium sulfate with warming to 21°C and then filtered and concentrated
to give 17.5 g of 1,3-di-O-benzyl-2-O-chloromethylglycerol.
To a solution of 1,3-di-O-benzyl-2-O-chloromethylglycerol (17.5 g, 55 mmol)
in 400 ml of DMF at 0°C under a drying tube was added sodium acetate (6 g).
The solution was then warmed to 21°C and magnetically stirred for 15 hours.
The solvent was removed by evaporation at reduced pressure and the oily
residue dissolved in 1 pound of diethylether. The ether solution was washed
once with 750 ml of water, two times with 250 ml of water, and once with 250
ml of brine, dried over sodium sulfate and concentrated to give 19 g of 2-Oacetoxymethyl-1,3-di-O-benzylglycerol as an oil.
Guanine (20 g, 0.132 mol) was combined with 300 ml of acetic anhydride and
the mixture heated at reflux for 16 hours. The mixture was cooled and the
excess acetic anhydride removed by evaporation at reduced pressure. The
residue was recrystallized from dimethyl sulfoxide to give 25.6 g of N2,9-
diacetylguanine.
N2,9-Diacetylguanine (15.61 g, 66 mmol), 2-O-acetoxymethyl-1,3-di-Obenzylglycerol (19 g, 55 mmol), and bis(p-nitrophenyl)phosphate (0.5 g) were
stirred together with 150 ml of diethylether. The solvent was removed by
evaporation and the residue heated in a 175°C oil bath for 1.5 hours under a
stream of nitrogen. Column chromatography eluting with 1:9
methanol/methylene chloride followed by recrystallization from ethyl acetate
afforded 4.76 g of N2,9-acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine,
melting point 145-146°C.
To a solution of N2,9-acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine
(4.62 g, 9.67 mmol) in 150 ml of methanol plus 40 ml of water was added
20% palladium hydroxide on carbon as a slurry in 10 ml of water. The mixture
was hydrogenated on a Parr hydrogenator at 60 psi of hydrogen for 38 hours
then filtered through celite and concentrated to a white solid. Recrystallization
from methanol/ethyl acetate gave 1.4 g of N2,9-acetyl-9-(1,3-dihydroxy-2-
propoxymethyl)guanine,melting point 205-208°C.
The mother liquor was further reduced with 10% palladium on carbon (1 g) in
150 ml of methanol plus 50 ml of water at 60 psi for 47 hours. The total yield
of N2,9-acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine was 2.11 g.
N2,9 -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine (721.9 mg, 2.4
mmol) was stirred with 50 ml of methanolic ammonia solution (methanol
saturated with ammonia at 0°C) for 17 hours at 21°C. The solution was
concentrated to a white solid and the residue recrystallized from methanol to
give 582.3 mg of 9-(1,3-dihydroxy-2-propoxymethyl)-guanine, melting point
250°C (decomp.).
brand name
Cytovene (Roche); Vitrasert (Bausch & Lomb);Cymevene.
Therapeutic Function
Antiviral
Acquired resistance
Prolonged, repeated courses lead to the selection of resistant strains, occurring in 8% of patients receiving the drug for >3 months. Studies of laboratory-derived resistant strains indicate that drug resistance can result from alterations in the phosphonotransferase encoded by the gene region UL 27, the viral DNA polymerase (gene region UL 54), or both.
General Description
Ganciclovir, 9-[(1,3-dihydroxy-2-propoxy) methyl]guanine)or DHPG (Cytovene), is an analog of acyclovir, with an additional hydroxymethyl group on the acyclic side chain.
After administration, similar to acyclovir, ganciclovir isphosphorylated inside the cell by a virally encoded proteinkinase to the monophosphate.Host cell enzymes catalyzethe formation of the triphosphate, which reaches more than10-fold higher concentrations in infected cells than in uninfectedcells.
The clinical usefulness of ganciclovir is limited by thetoxicity of the drug. Ganciclovir causes myelosuppression,producing neutropenia, thrombocytopenia, and anemia.These effects are probably associated with inhibition of hostcell DNA polymerase.Potential central nervous systemside effects include headaches, behavioral changes, and convulsions.Ganciclovir is mutagenic, carcinogenic, and teratogenicin animals.
Pharmaceutical Applications
A synthetic 2′-deoxyguanosine nucleoside analog, supplied as the l-valine ester, valganciclovir, for oral administration and as the sodium salt for parenteral use. A slow-release ocular implant device is also available.
Biochem/physiol Actions
Cell permeable: yes
Mechanism of action
Ganciclovir sodium is an acyclic deoxyguanosine analogue of acyclovir. Ganciclovir inhibits DNA polymerase. Its active form is ganciclovir triphosphate, which is an inhibitor of viral rather than of cellular DNA polymerase. The phosphorylation of ganciclovir does not require a virus-specific thymidine kinase for its activity against CMV. The mechanism of action is similar to that of acyclovir; however, ganciclovir is more toxic than acyclovir to human cells.
Pharmacology
Activation of ganciclovir first requires conversion to ganciclovir monophosphate by viral enzymes: protein kinase pUL97 in CMV or thymidine kinase in HSV. Host cell enzymes then perform two additional phosphorylations. The resultant ganciclovir triphosphate competes with dGTP for access to viral DNA polymerase. Its incorporation into the growing DNA strand causes chain termination in a manner similar to that of acyclovir. Ganciclovir triphosphate is up to 100-fold more concentrated in CMV-infected cells than in normal cells and is preferentially incorporated into DNA by viral polymerase. However, mammalian bone marrow cells are sensitive to growth inhibition by ganciclovir.
Pharmacokinetics
Oral absorption, ganciclovir: c. 5.4–7.1%
valganciclovir: 80%
Cmax 5 mg/kg 1-h infusion: 33.2 μmol end infusion
Plasma half-life (intravenous infusion): 2.9 h
Volume of distribution: c. 1.17 L/kg
Plasma protein binding: 1–2%
Absorption
After an intravenous infusion of 5 mg/kg, the plasma level after 11 h was 2.2 μmol. After repeated 5 mg/kg doses every 8 h, the mean peak serum levels were 25 μmol and mean trough levels 3.6 μmol, levels in excess of, or in the same range as, the ID50 for CMV. In patients treated for 8–22 days with 1 or 2.5 mg/kg every 8 h, the mean steady-state plasma concentrations after a 1 h infusion of 1 mg/kg ranged from 7.2 μmol immediately after infusion to 0.8 μmol after 8 h. Corresponding values after a dose of 2.5 mg/kg were 19.6 and 3.2 μmol, respectively. Multiple dosing with oral ganciclovir 1 g every 8 h resulted in peak levels of 1.1 mg/L (4.3 μmol) and a trough of 0.52 mg/L (2.1 μmol). Valganciclovir is rapidly converted to ganciclovir, doses of 900 mg producing plasma levels similar to those achieved with 5 mg/kg ganciclovir every 12 h.
Distribution
Data on distribution are limited. The levels of the drug in CSF are estimated to be 24–67% of those in plasma. Mean intravitreal levels of 14 μmol were reported for samples taken a mean of 12 h after therapy with a mean dose of 6 mg/kg per day. However, no significant correlations are noted between time after the last dose and intravitreal concentration. The observed mean value in the eye is below the concentration required to achieve 50% or 90% inhibition of CMV plaque formation by clinical isolates, which may explain the difficulty in controlling CMV retinitis.
Metabolism and excretion
About 80% of the drug is eliminated unchanged in the urine within 24 h. Probenecid and other drugs that impact renal tubular secretion or absorption may reduce renal clearance. In severe renal impairment, the mean plasma half-life is 28.3 h. Dosage must be reduced in patients with impaired renal function. Plasma levels of the drug can be reduced by approximately 50–90% with hemodialysis. The half-life on dialysis is about 4 h. Patients undergoing dialysis should be given 1.25 mg/kg per day; therapy should also be administered after dialysis. No significant pharmacokinetic interaction occurs when ganciclovir and foscarnet are given as concomitant or daily alternate therapy.
Pharmacokinetics
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.
Clinical Use
Life- or sight-threatening CMV infections in immunocompromised individuals
Prevention and treatment of CMV disease in patients receiving
immunosuppressive therapy for organ transplantation
An ocular implant has been developed for the treatment of
CMV retinitis.
Use in congenital CMV infections has not yet gained regulatory
approval.
Clinical Use
Intravenous ganciclovir is indicated for the treatment of CMV retinitis in immunocompromised individuals, including those with AIDS, and for the prevention of CMV infection in organ transplant recipients.Oral ganciclovir is less effective than the intravenous preparation but carries a lower risk of adverse effects. It is Intravenous ganciclovir is indicated for the treatment of CMV retinitis in immunocompromised individuals, including those with AIDS, and for the prevention of CMV infection in organ transplant recipients.Oral ganciclovir is less effective than the intravenous preparation but carries a lower risk of adverse effects. It is
Side Effects
Myelosuppression is the most common serious adverse effect of ganciclovir treatment; therefore, patients’ blood counts should be closely monitored. Neutropenia and anemia have been reported in 25 to 30% of patients, and thrombocytopenia has been seen in 5 to 10%. Elevated serum creatinine may occur following ganciclovir treatment, and dosage adjustment is required for patients with renal impairment. In animal studies, ganciclovir causes decreased sperm production, teratogenesis, and tumor formation.
Side Effects
The 50% inhibitory concentration (IC50) for human bone marrow colony-forming cells is 39 (± 73) μmol; for other cell lines it ranges from 110 to 2900 μmol. Toxicity frequently limits therapy. Marrow suppression may develop on as little as 5 mg/kg on alternate days and is exacerbated when the drug is given with zidovudine. Neutropenia of <1000/mm3 occurs in nearly 40% of recipients and <500/mm3 in upwards of 30% for those given induction therapy of 10 mg/kg per day for 14 days, followed by 5 mg/kg per day. Neutropenia is reversible and develops during the early treatment or maintenance phase, but may occur later. Thrombocytopenia of <20 000/mm3 and <50 000/mm3 develops in about 10% and 19% of patients, respectively. Frequent monitoring of the full blood count is recommended.
Adverse effects on the CNS, including confusion, convulsions, psychosis, hallucinations, tremor, ataxia, coma, dizziness, headaches and somnolence, occur in around 5% of patients. Liver function abnormalities, fever and rash occur in about 2%. Intraocular injection of ganciclovir is associated with intense pain, and occasionally amaurosis lasting for 1–10 min.
Animal studies indicate that inhibition of spermatogenesis and suppression of female fertility occurs. Ganciclovir is also potentially embryolethal, mutagenic and teratogenic, and is contraindicated during pregnancy or lactation. It can cause local tissue damage and should not be administered intramuscularly or subcutaneously; patients should be adequately hydrated during treatment.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: increased risk of convulsions with
imipenem/cilastatin.
Antivirals: possibly increased didanosine
concentration; profound myelosuppression with
zidovudine - avoid if possible.
Increased risk of myelosuppression with other
myelosuppressive drugs.
Mycophenolate: concomitant treatment with
ganciclovir and mycophenolate causes increased
concentration of ganciclovir and inactive
mycophenolate metabolite.
Metabolism
Renal excretion of unchanged drug by glomerular filtration and active tubular secretion is the major route of elimination of ganciclovir. In patients with normal renal function, 89.6 ± 5.0% of IV administered ganciclovir was recovered unmetabolised in the urine.
Metabolism
Little to no metabolism, about 90% of plasma ganciclovir is eliminated unchanged in the urine.
Purification Methods
Recrystallise gangcyclovir from MeOH. Alternatively dissolve 90g of it in 700mL of 2O, filter and cool (ca 94% recovery). UV: max in MeOH 254nm ( 12,880), 270sh nm ( 9,040); its solubility in 2O at 25o is 4.3mg/mL at pH 7.0. ANTIVIRAL. [Ogilvie et al. Can J Chem 60 3005 1982, Ashton et al. Biochem Biophys Res Commun 108 1716 1982, Martin et al. J Med Chem 26 759 1983.]
Precautions
Ganciclovir interacts with a number of medications,some of which are used to treat HIV or transplant patients.Ganciclovir may cause severe neutropenia whenused in combination with zidovudine. Ganciclovir increasesserum levels of didanosine, whereas probeneciddecreases ganciclovir elimination. Nephrotoxicity mayresult if other nephrotoxic agents (e.g., amphotericin B,cyclosporine, NSAIDs) are administered in conjunctionwith ganciclovir.
References
[1] ding z1, mathur v, ho pp, james ml, lucin km, hoehne a, alabsi h, gambhir ss, steinman l, luo j, wyss-coray t. antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation. j exp med. 2014 feb 10; 211(2):189-98.
Properties of Ganciclovir
Melting point: | 250°C |
Boiling point: | 398.46°C (rough estimate) |
Density | 1.3559 (rough estimate) |
refractive index | 1.7610 (estimate) |
Flash point: | 9℃ |
storage temp. | 2-8°C |
solubility | 0.1 M HCl: 10 mg/mL |
form | powder |
pka | 9.33±0.20(Predicted) |
color | white |
Water Solubility | 3.6g/L(25 ºC) |
Merck | 14,4363 |
InChI | 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) |
CAS DataBase Reference | 82410-32-0(CAS DataBase Reference) |
Safety information for Ganciclovir
Signal word | Danger |
Pictogram(s) |
Health Hazard GHS08 |
GHS Hazard Statements |
H340:Germ cell mutagenicity |
Precautionary Statement Codes |
P201:Obtain special instructions before use. P308+P313:IF exposed or concerned: Get medical advice/attention. |
Computed Descriptors for Ganciclovir
InChIKey | IRSCQMHQWWYFCW-UHFFFAOYSA-N |
SMILES | N1C2=C(N=C(N)NC2=O)N(COC(CO)CO)C=1 |
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