Valganciclovir

Curran, Monique P; Noble, Stuart

doi:10.2165/00003495-200161080-00013

Cited by 101 publications

(57 citation statements)

References 12 publications

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“…Recently, amino acid ester prodrugs of nucleoside analogs such as valacyclovir (VACV) and valganciclovir (VGCV) have been shown to significantly increase their oral absorption (5)(6)(7)(8). The valyl ester prodrug of acyclovir (ACV), valacyclovir, increases the oral bioavailability of ACV 3-to 5-fold (9).…”

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confidence: 99%

Identification of a Human Valacyclovirase

Kim¹,

Chu²,

Kim³

et al. 2003

Journal of Biological Chemistry

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Valacyclovir is the 5-valyl ester prodrug of acyclovir, an effective anti-herpetic drug. Systemic availability of acyclovir in humans is three to five times higher when administered orally as the prodrug. The increased bioavailability of valacyclovir is attributed to carrier-mediated intestinal absorption, via the hPEPT1 peptide transporter, followed by the rapid and complete conversion to acyclovir. The one or more human enzymes responsible for in vivo activation of the prodrug to the active drug and its conversion sites, however, have not been identified. In this report, we describe the purification, identification, and characterization of a human enzyme that activates valacyclovir to acyclovir. A protein with significant hydrolytic activity toward valacyclovir, the 5-glycyl ester of acyclovir, and the 5-valyl ester of zidovudine (AZT), was purified from Caco-2 cells derived from human intestine. Using a non-redundant data base search, the N-terminal 19-amino acid sequence of the purified 27-kDa, basic protein revealed a perfect match within the N terminus of a serine hydrolase, Biphenyl hydrolase-like (BPHL, gi:4757862) protein, previously cloned from human breast carcinoma. Recombinant BPHL exhibited significant hydrolytic activity for both valacyclovir and valganciclovir with specificity constants (k cat /K m ), 420 and 53.2 mM ؊1 ⅐s ؊1 , respectively. We conclude that BPHL may be an important enzyme activating valacyclovir and valganciclovir in humans and an important new target for prodrug design.Prodrugs of therapeutically active agents have been used to improve pharmaceutical, biopharmaceutical, and pharmacokinetic properties of numerous active therapeutic agents. Prodrugs are designed to be inactive until in vivo activation to the parent drug, and hence reliable in vivo activation of the prodrug is considered critical for their pharmacological activity (1). Identification of the mechanism of in vivo activation of prodrugs is important for prodrug design and for investigating clinical applications. Furthermore, design and development of prodrugs for humans has been significantly hampered by the unknown species differences in the activating enzymes. Thus, identification of the one or more prodrug-activating enzymes will significantly aid in the selection of animal models for human drug development.The participation of peptidases or esterases in prodrug activation will depend on the pro-moiety, its linker to the parent drug, as well as the parent drug. For several prodrugs, their in vivo activation mechanism has been studied in more detail. For example, the anti-cancer prodrug, CPT-11 (irinotecan), a carbamate derivative of 7-ethyl-10-hydroxycamptothecin, is converted to its active metabolite, 7-ethyl-10-hydroxycamptothecin by human carboxylesterases. The efficiency of hydrolysis varies depending on isoforms such that carboxylesterase 2 (hCE2) 1 and intestinal carboxylesterase (hiCE) are more efficient activators than human liver carboxylesterase 1 (hCE1) (2-4). The angiotensin-converting enzyme inhibitor...

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confidence: 99%

Identification of a Human Valacyclovirase

Kim¹,

Chu²,

Kim³

et al. 2003

Journal of Biological Chemistry

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“…They include ganciclovir (10), its prodrug valganciclovir (11), cidofovir (18), foscarnet (9), and the phosphorothioate oligonucleotide complementary to HCMV IE2 mRNA, fomivirsen (29). There are disadvantages associated with the use of each of these drugs, including poor oral bioavailability and toxicity (2,10,12,18).…”

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confidence: 99%

Resistance of Human Cytomegalovirus to the Benzimidazole l -Ribonucleoside Maribavir Maps to UL27

Komazin

Ptak

Emmer

et al. 2003

J Virol

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1-(␤-D-Ribofuranosyl)-2,5,6-trichlorobenzimidazole (TCRB) and its 2-bromo analog, BDCRB, are potent and selective inhibitors of human cytomegalovirus (HCMV) DNA processing and packaging. Since they are readily metabolized in vivo, analogs were synthesized to improve biostability. One of these, 1-(␤-L-ribofuranosyl)-2-isopropylamino-5,6-dichlorobenzimidazole (1263W94; maribavir), inhibits viral DNA synthesis and nuclear egress. Resistance to maribavir was mapped to UL97, and this viral kinase was shown to be a direct target of maribavir. In the present study, an HCMV strain resistant to TCRB and BDCRB was passaged in increasing concentrations of maribavir, and resistant virus was isolated. This strain (G2) grew at the same rate as the wild-type virus and was resistant to both BDCRB and maribavir. Resistance to BDCRB was expected, because the parent strain from which G2 was isolated was resistant due to known mutations in UL56 and UL89. However, no mutations were found in UL97 or other relevant open reading frames that could explain resistance to maribavir. Because sequencing of selected HCMV genes did not identify the resistance mutation, a cosmid library was made from G2, and a series of recombinant G2 wild-type viruses were constructed. Testing the recombinants for sensitivity to maribavir narrowed the locus of resistance to genes UL26 to UL32. Sequencing identified a single coding mutation in ORF UL27 (Leu335Pro) as the one responsible for resistance to maribavir. These results establish that UL27 is either directly or indirectly involved in the mechanism of action of maribavir. They also suggest that UL27 could play a role in HCMV DNA synthesis or egress of HCMV particles from the nucleus.

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“…La biodisponibilidad del ganciclovir VO es muy pobre, lo que le resta eficacia con respecto al ganciclovir IV y obliga a los pacientes a tomar un gran número de comprimidos 20 . El valganciclovir, sin embargo, se metaboliza por enzimas del tubo digestivo y se transforma prácticamente en un 100% en ganciclovir 21 . En un ensayo clínico aleatorizado y abierto llevado a cabo con 160 pacientes con sida y retinitis por CMV recién diagnosticada se ha comprobado que el valganciclovir VO es tan eficaz como el ganciclovir IV como tratamiento de inducción y resulta muy cómodo y eficaz para la fase de mantenimiento 12 .…”

Section: Profilaxis Secundariaunclassified

Prevención de las infecciones oportunistas en pacientes adultos y adolescentes infectados por el VIH. Recomendaciones de GESIDA/Plan Nacional sobre el Sida. Año 2003

Berenguer¹,

Laguna²,

López‐Aldeguer³

et al. 2004

Enferm Infecc Microbiol Clin

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OBJETIVO. Actualización de las recomendaciones del Grupo de Estudio de Sida (GESIDA) y la Secretaría del Plan Nacional sobre el Sida (PNS) sobre prevención de las infecciones oportunistas en pacientes adultos y adolescentes infectados por el virus de la inmunodeficiencia humana (VIH).MÉTODOS. Las recomendaciones han sido consensuadas por un grupo de expertos de GESIDA y/o del PNS tras la revisión del antiguo documento y las aportaciones científicas sobre la materia de los últimos años. Para la clasificación de la fuerza y de la calidad de las recomendaciones se ha seguido el sistema utilizado por la Sociedad Americana de Enfermedades Infecciosas (IDSA) y el Servicio de Salud Pública de los Estados Unidos de América (USPHS). RESULTADOS. En este documento, se realiza una revisión pormenorizada de las medidas para prevenir las infecciones causadas por virus, bacterias, hongos y parásitos en el contexto de la infección por el VIH. Para cada grupo de patógenos se han dado recomendaciones para prevenir la exposición a los mismos, para las profilaxis primarias y para las profilaxis secundarias. También se han establecido unos criterios para la retirada de las profilaxis en pacientes que tienen una buena respuesta al tratamiento antirretroviral de gran actividad (TARGA). CONCLUSIONES. El TARGA es la mejor estrategia para prevenir las infecciones oportunistas en pacientes infectados por el VIH. Sin embargo, las profilaxis continúan siendo necesarias en los países con pocos recursos económicos, en pacientes muy

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Valganciclovir

Cited by 101 publications

References 12 publications

Identification of a Human Valacyclovirase

Identification of a Human Valacyclovirase

Resistance of Human Cytomegalovirus to the Benzimidazole l -Ribonucleoside Maribavir Maps to UL27

Prevención de las infecciones oportunistas en pacientes adultos y adolescentes infectados por el VIH. Recomendaciones de GESIDA/Plan Nacional sobre el Sida. Año 2003

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