O, inhaled, IV* Topical
*Not currently approved for use in USA.
ABBREVIATIONS: IV, intravenous; O, oral; T, topical; ophth, ophthalmic.
Acyclovir resistance results from three mechanisms: absence or partial production of viral TK, altered TK substrate specificity (e.g., phosphorylation of thymidine but not acyclovir), or altered viral DNA polymerase. Resistant variants are present in native virus populations, and heterogeneous mixtures of viruses occur in isolates from treated patients. The most common resistance mechanism in clinical HSV isolates is absent or deficient viral TK activity; viral DNA polymerase mutants are rare. Resistance typically is defined by inhibitory concentrations of >2-3 ^g/mL, which predict failure of therapy in immunocompromised patients.
Similarly, acyclovir resistance in VZV isolates is caused by mutations in its TK or polymerase.
ABSORPTION, DISTRIBUTION, AND ELIMINATION
Oral bioavailability of acyclovir (~10-30%) decreases with increasing dose. Valacyclovir is converted rapidly and virtually completely to acyclovir after oral administration. This conversion reflects firstpass intestinal and hepatic metabolism by enzymatic hydrolysis. Unlike acyclovir, valacyclovir is a substrate for intestinal and renal peptide transporters. The oral bioavailability of acyclovir increases to ~70%o following valacyclovir administration. Peak acyclovir concentrations occur ~2 hours after dosing. Peak plasma concentrations of valacyclovir are only 4% of acyclovir levels. Less than 1% of an administered dose of valacyclovir is recovered in the urine, and most is eliminated as acyclovir.
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