mechanisms of action and resistance Foscarnet inhibits viral nucleic acid synthesis by interacting directly with herpesvirus DNA polymerase or HIV reverse transcriptase (Figure 49-1A). It is taken up slowly by cells and does not undergo significant intracellular metabolism. Foscarnet reversibly and noncompetitively blocks the pyrophosphate binding site of the viral polymerase and inhibits pyrophosphate cleavage from deoxynucleotide triphosphates. Foscarnet has ~100-fold greater inhibitory effects against herpesvirus DNA polymerases than against cellular DNA polymerase a. Herpesviruses resistant to foscarnet have point mutations in the viral DNA polymerase that reduce foscarnet activity.
ABSORPTION, DISTRIBUTION, AND ELIMINATION
Vitreous levels approximate those in plasma, and CSF levels average 66% of those in plasma.
Over 80% of foscarnet is excreted unchanged in the urine. Plasma clearance is proportional to creatinine clearance, and dose adjustments are indicated for small decreases in renal function. Plasma elimination is complex, with an initial t/2 of 4-8 hours and a prolonged terminal t/2 of 4 days. Sequestration in bone with gradual release accounts for a ~10-20% of a given dose. Foscarnet is cleared efficiently by hemodialysis (~50% of a dose).
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