DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

O
N
HN
H N N
2 N
OH CH 2
O
CH 2 CH 2
ACYCLOVIR
H 2 N
HN
O
N
NH 2
N
N
N
O
N O
O NH 2
HO P O
CH 2 OCH 2 CH 2 OC C CH(CH 3 ) 2 HO
H
OH
VALACYCLOVIR CIDOFOVIR FOSCARNET
HO
O
P C
OH
O
OH
1597
CHAPTER 58
H 2 N
N
O
N
H
OH
PENCICLOVIR
O
N
N
OH
HN
N
H 2 N N N
HO CH 2 CH 2
HC O
HO CH 2
GANCICLOVIR
HO
OH
H 2 N
HN
O
N
OH
N
NH 2
O
N O
O
VALGANCICLOVIR
ANTIVIRAL AGENTS (NONRETROVIRAL)
I
NH
O
HO
O
N
O
N
O
F
NH
OH
F
F O
IDOXURIDINE
TRIFLURIDINE
Figure 58–2. Chemical Structures of Anti-Herpes Drugs.
typically is defined by in vitro inhibitory concentrations of >2-3
μg/mL, which predict failure of therapy in immunocompromised
patients.
Acyclovir resistance in VZV isolates is caused by mutations
in VZV thymidine kinase and less often by mutations in viral DNA
polymerase.
Absorption, Distribution, and Elimination. The oral bioavailability
of acyclovir ranges from 10-30% and decreases with increasing
dose (Wagstaff et al., 1994). Peak plasma concentrations average
0.4-0.8 μg/mL after 200-mg doses and 1.6 μg/mL after 800-mg
doses. Following intravenous dosing, peak and trough plasma concentrations
average 9.8 and 0.7 μg/mL after 5 mg/kg every 8 hours
and 20.7 and 2.3 μg/mL after 10 mg/kg every 8 hours, respectively.
Valacyclovir is converted rapidly and virtually completely to
acyclovir after oral administration in healthy adults. This conversion
is thought to result from first-pass intestinal and hepatic metabolism
through enzymatic hydrolysis. Unlike acyclovir, valacyclovir is a
substrate for intestinal and renal peptide transporters. The relative
oral bioavailability of acyclovir increases 3-5 fold to ~70% following
valacyclovir administration (Steingrimsdottir et al., 2000). Peak
acyclovir concentrations average 5-6 μg/mL following single 1000-
mg doses of oral valacyclovir and 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; most is eliminated as acyclovir.
Acyclovir distributes widely in body fluids, including vesicular
fluid, aqueous humor, and cerebrospinal fluid (CSF). Compared
with plasma, salivary concentrations are low, and vaginal secretion
concentrations vary widely. Acyclovir is concentrated in breast milk,
amniotic fluid, and placenta. Newborn plasma levels are similar to
maternal ones. Percutaneous absorption of acyclovir after topical
administration is low.
The mean plasma elimination t 1/2
of acyclovir is ~2.5 hours
(range: 1.5-6 hours in adults with normal renal function). The elimination
t 1/2
of acyclovir is ~4 hours in neonates and increases to 20
hours in anuric patients (Wagstaff et al., 1994). Renal excretion of
unmetabolized acyclovir by glomerular filtration and tubular