124832-26-4 Usage
Originator
Valcivir,Cipla Limited
Indications
Valacyclovir (Valtrex) is the 1-valine ester (prodrug) of acyclovir that exhibits
no activity until hydrolyzed in the intestinal wall or liver to acyclovir and its
active metabolite. Its modified structure allows increased intestinal absorption
and concomitant higher plasma levels of acyclovir. It demonstrates activity
against HSV types 1 and 2, varicella-zoster virus, and cytomegalovirus.
It exerts its effects by interfering with DNA synthesis through phosphorylation
by viral thymidine kinase and subsequent inhibition of viral DNA
polymerase, thereby inhibiting viral replication. Valtrex is indicated for the
treatment of acute herpes zoster and recurrent genital herpes in immunocompetent
adults. The most common side effects are headache, nausea, and
vomiting.Valacyclovir is the only antiviral agent approved for herpes labialis,
for a 3-day course in the episodic treatment of recurrent genital herpes (2).
Valacyclovir is indicated for recurrent genital herpes and is administered at
500 mg twice daily for 3 days at the onset of prodromal symptoms or at the first
sign of infection.
Manufacturing Process
By dicyclohexylcarbodiimide catalyzed esterification of acyclovir (6H-purin-6-
one, 1,9-dihydro-2-amino-9-((2-hydroxyethoxy)methyl)-) with the butyloxycarbonyl valine. Treatment of ester obtained with trifluoroacetic acid
leads to scission of the BOC group to provide L-valine ester with 9-((2-
hydroxyethoxy)methyl)guanine (valacyclovir).
Therapeutic Function
Antiviral
Biological Activity
valacyclovir, the metabolic precursor of , is now approved for treatment and prevention of genital infection with herpes simplex viruses [1]. in vitro: vacv uptake was concentration dependent and saturable with a michaelis-menten constant and maximum velocity of 1.64 +/- 0.06 mm and 23.34 +/- 0.36 nmol/mg protein/5 min, respectively. a very similar km value was obtained in hpept1/cho cells and in rat and rabbit tissues and caco-2 cells, suggesting that hpept1 dominates the intestinal transport properties of vacv in vitro [5].
Pharmacology
Valacyclovir (Valtrex), a valine ester prodrug of acyclovir, has
a bioavailability three to five times that of acyclovir. This is due to its improved
gastrointestinal absorption compared to acyclovir. Valacyclovir is rapidly and
almost completely converted to acyclovir after oral administration, with levels
comparable to those of intravenous acyclovir. This allows for twice-daily dosing,
which may improve compliance and ultimate clinical efficacy. It is more costly
than acyclovir.
Clinical Use
Antiviral: Herpes zoster and simplex Prevention of cytomegalovirus (CMV) disease after renal transplantation
in vivo
for treatment of a first episode of genital herpes, a large comparative trial has shown that valacyclovir (1 g twice a day) is as effective as acyclovir (200 mg five times a day) when given for 10 days. for treating recurrences, two trials show that valacyclovir is as effective as acyclovir (200 mg five times a day) with a treatment period of 5 days. a daily dose of 1 g of valacyclovir is as effective as 2 g daily. valacyclovir can be administered once a day[1]. the concentrations of acyclovir in serum and csf were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day [2]. ec50 values of pe and ac in 3t3 cells were 0.02 and 0.01 ug/ml, while values in bhk cells were 0.2 and 0.03 ug/ml. treatment of infected immunosuppressed mice and fa and va (b.i.d., 5.5 days) reduced the proportion with erythema from 100% to 24% and 38%, and eliminated ear paralysis, ear lesions (vesicles, etc) and death. virus was absent from ear and brainstem by day 6, but reappeared after discontinuation in mice treated with va [3].
Drug interactions
Potentially hazardous interactions with other drugs Ciclosporin: may alter ciclosporin levels; possibly
increased risk of nephrotoxicity.
Mycophenolate: higher concentrations of both
aciclovir and mycophenolic acid on concomitant
administration.
Tacrolimus: possibly increased risk of nephrotoxicity
IC 50
value: 2.9 microg/ml (for hsv-1 w)[4]. valacyclovir, the metabolic precursor of , is now approved for treatment and prevention of genital infection with herpes simplex viruses [1]. in vitro: vacv uptake was concentration dependent and saturable with a michaelis-menten constant and maximum velocity of 1.64 +/- 0.06 mm and 23.34 +/- 0.36 nmol/mg protein/5 min, respectively. a very similar km value was obtained in hpept1/cho cells and in rat and rabbit tissues and caco-2 cells, suggesting that hpept1 dominates the intestinal transport properties of vacv in vitro [5]. in vivo: for treatment of a first episode of genital herpes, a large comparative trial has shown that valacyclovir (1 g twice a day) is as effective as acyclovir (200 mg five times a day) when given for 10 days. for treating recurrences, two trials show that valacyclovir is as effective as acyclovir (200 mg five times a day) with a treatment period of 5 days. a daily dose of 1 g of valacyclovir is as effective as 2 g daily. valacyclovir can be administered once a day[1]. the concentrations of acyclovir in serum and csf were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day [2]. ec50 values of pe and ac in 3t3 cells were 0.02 and 0.01 ug/ml, while values in bhk cells were 0.2 and 0.03 ug/ml. treatment of infected immunosuppressed mice and fa and va (b.i.d., 5.5 days) reduced the proportion with erythema from 100% to 24% and 38%, and eliminated ear paralysis, ear lesions (vesicles, etc) and death. virus was absent from ear and brainstem by day 6, but reappeared after discontinuation in mice treated with va [3].
Metabolism
Valaciclovir is readily absorbed from the gastrointestinal
tract after oral doses, and is rapidly and almost completely
converted to aciclovir and valine by first-pass intestinal or
hepatic metabolism.
Aciclovir is converted to a small extent to the metabolites
9(carboxymethoxy)methylguanine (CMMG) by alcohol
and aldehyde dehydrogenase and to 8-hydroxy-aciclovir
(8-OH-ACV) by aldehyde oxidase. Approximately 88%
of the total combined plasma exposure is attributable
to aciclovir, 11% to CMMG and 1% to 8-OH-ACV.
Valaciclovir is eliminated mainly as aciclovir and its
metabolite 9- CMMG; less than 1% of a dose of
valaciclovir is excreted unchanged in the urine.
Toxicity evaluation
In general, the adverse reactions with valaciclovir are similar to those seen with its active metabolite, aciclovir. Preclinical toxicology studies with valaciclovir toxicology studies in animals showed no toxicity separate to that expected from the active metabolite. In a phase 1 study of valaciclovir dosed at either 1 or 2 g four times daily for 30 days, the main reported side-effects were gastrointestinal, with nausea, vomiting, diarrhea, and abdominal pain in up to onethird of patients; no renal or neurologic side-effects were notetoxd, but four patients developed grade 3 or 4 neutropenia. None of the sideeffects observed appeared to be drug related.
Check Digit Verification of cas no
The CAS Registry Mumber 124832-26-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,4,8,3 and 2 respectively; the second part has 2 digits, 2 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 124832-26:
(8*1)+(7*2)+(6*4)+(5*8)+(4*3)+(3*2)+(2*2)+(1*6)=114
114 % 10 = 4
So 124832-26-4 is a valid CAS Registry Number.
InChI:InChI=1/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1
124832-26-4Relevant articles and documents
Topical iontophoretic delivery of ionizable, biolabile aciclovir prodrugs: A rational approach to improve cutaneous bioavailability
Chen, Yong,Alberti, Ingo,Kalia, Yogeshvar N.
, p. 103 - 113 (2016/01/15)
The objective was to investigate the topical iontophoretic delivery of a series of amino acid ester prodrugs of aciclovir (ACV-X, where ACV = aciclovir and X = Arg, Gly, Ile, Phe, Trp and Val) as a means to enhance cutaneous delivery of ACV. The newly synthesized prodrugs were characterized by 1H NMR and high resolution mass spectrometry. Analytical methods using HPLC-UV were developed for their quantification and each method was validated. Investigation of solution stability as a function of pH showed that all ACV-X prodrugs were relatively stable in acid conditions at pH 2.0 and pH 5.5 for up to 8 h but susceptible to extensive hydrolysis at pH 7.4 and under alkaline conditions (pH 10). No ACV-X hydrolysis was observed after contact for 2 h with the external surface of porcine stratum corneum. However, there was significant hydrolysis following contact with the dermal surface of dermatomed porcine skin, in particular, for ACV-Arg. Passive transport of ACV and ACV-X prodrugs from aqueous solution after 2 h was below the limit of detection. Iontophoresis of ACV at 0.5 mA/cm2 for 2 h led to modest ACV skin deposition (QDEP,ACV) of 4.6 ± 0.3 nmol/cm2. In contrast, iontophoresis of ACV-X prodrugs under the same conditions produced order of magnitude increases in cutaneous deposition of ACV species, that is, QDEP,TOTAL = QDEP,ACV + QDEP,ACV-X. QDEP,TOTAL for ACV-Gly, ACV-Val, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Arg was 412.8 ± 44.0, 358.8 ± 66.8, 434.1 ± 68.2, 249.8 ± 81.4, 156.1 ± 76.3, 785.9 ± 78.1 nmol/cm2, respectively. The extent of bioconversion of ACV-X to ACV in the skin was high and the proportion of ACV present ranged from 81% to 100%. The skin retention ratio, a measure of the selectivity of ACV species for deposition over permeation after iontophoretic delivery of ACV-X prodrugs, was dependent on both the rate of transport and the susceptibility to hydrolysis of the prodrugs. Skin deposition of ACV and its six prodrugs were investigated further as a function of current density (0.125, 0.25 and 0.5 mA/cm2); the effect of duration of current application (5, 10, 30, 60 and 120 min) was evaluated using ACV-Arg and ACV-Ile. Iontophoresis of ACV-Arg and ACV-Ile at 0.25 mA/cm2 for only 5 min resulted in the deposition of appreciable amounts of ACV (36.4 ± 5.7 nmol/cm2 and 40.3 ± 6.1 nmol/cm2, respectively), corresponding to supra-therapeutic average concentrations in skin against HSV-1 or HSV-2. The results demonstrated that cutaneous bioavailability of ACV could be significantly improved after short-duration iontophoresis of ionizable, biolabile ACV-X prodrugs.
Liquid chromatographic resolution of amino acid esters of acyclovir including racemic valacyclovir on crown ether-based chiral stationary phases
Ahn, Seong Ae,Hyun, Myung Ho
, p. 268 - 273 (2015/03/18)
Valacyclovir, a potential prodrug for the treatment of patients with herpes simplex and herpes zoster, and its analogs were resolved on two chiral stationary phases (CSPs) based on (3,3′-diphenyl-1,1′-binaphthyl)-20-crown-6 covalently bonded to silica gel. In order to find out an appropriate mobile phase condition, various mobile phases consisting of various organic modifiers in water containing various acidic modifiers were applied to the resolution of valacyclovir and its analogs. When 30% acetonitrile in water containing any of 0.05 M, 0.10 M, or 0.15 M perchloric acid was used as a mobile phase, valacyclovir and its analogs were resolved quite well on the two CSPs with the separation factors (α) in the range of 2.49～6.35 and resolutions (RS) in the range of 2.95 ～ 12.21. Between the two CSPs, the CSP containing residual silanol protecting n-octyl groups on the silica surface was found to be better than the CSP containing residual silanol groups.
Crystalline forms of valacyclovir hydrochloride
-
, (2008/06/13)
Provided are novel crystalline forms of valacyclovir hydrochloride, in particular a novel hydrated form of valacyclovir hydrochloride having about 6% to about 10% by weight water. Also provided are methods for making the novel crystalline forms.
Crystalline forms of valacyclovir hydrochloride
-
, (2008/06/13)
Provided are novel polymorphs and pseudopolymorphs of valacyclovir hydrochloride and pharmaceutical compositions containing these. Also provided are methods for making the novel polymorphs and pseudopolymorphs, which include valacyclovir hydrochloride monohydrate and valacyclovir hydrochloride dihydrate.
Azetidinone derivatives for the treatment of HCMV infections
-
, (2008/06/13)
A compound of formula 1: wherein Y is S or O; R1is C1-6alkyl; (C0-6alkyl)aryl; (C0-6alkyl)Het; or R1is an amino acid analog or dipeptide analog of the formula: wherein R2is H, C1-10alkyl; or an amide or ester group; A is C6-10aryl, Het or CH—R3wherein R3is C1-6alkyl or (C0-4alkyl)aryl; and Z is H, C1-6alkyl, or an acyl; R4is hydrogen, lower alkyl, methoxy, ethoxy, or benzyloxy; and R5is alkyl, cycloalkyl, carboxyl group; an aryl; Het or Het(lower alkyl); or R4and R5together with the nitrogen atom to which they are attached form a nitrogen containing ring optionally substituted with phenyl or C(O)OCH2-phenyl, said phenyl ring optionally mono- or di-substituted with among others C(O)OR7wherein R7is lower alkyl or phenyl(lower alkyl); or a therapeutically acceptable acid addition salt thereof which compounds are useful in the treatment of HCMV infections.
Therapeutic valine esters of acyclovir and pharmaceutically acceptable salts thereof
-
, (2008/06/13)
The present invention relates to certain amino acid exters of the purine nucleoside acyclovir, pharmaceutically acceptable salts thereof and their use in the treatment of herpes virus infections. The invention also includes pharmaceutical formulations and processes for the preparation of such compounds.
