Ganciclovir and Valganciclovir

Ganciclovir (Cytovene) is an acyclic analogue of 2'de-oxyguanosine with inhibitory activity toward all herpesviruses, especially CMV. Valganciclovir (Valcyte) is the L-valyl ester prodrug of ganciclovir. 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 poly-merase. However, mammalian bone marrow cells are sensitive to growth inhibition by ganciclovir.

Resistance to ganciclovir has been found in individuals exposed to the drug for long periods and in people who have never been treated with this agent. The principal mechanism of resistance is mutation of the protein kinase gene. Mutations in the DNA polymerase have been seen more rarely.

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