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

1614
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
O
NH 2
H 2 N
N
H 2 N
N
N
N N
N
N
S
N N O
O
OH
O
O
O P OH
H H
H
H
OH
OH OH
HO
CH 3
RIBAVIRIN LAMIVUDINE TENOFOVIR
OH
CH 3 O
CH
N
3
N
HN
OH
N N O
O
H
N
2 N N N CH 2
O
O P OH
HN
N
OH
O
OH
ENTECAVIR
ADEFOVIR
TELBIVUDINE
Figure 58–6. Chemical Structures of the Anti-Hepatitis Drugs.
OH
Intracellular phosphorylation to the mono-, di-, and
triphosphate derivatives is mediated by host cell
enzymes. In both uninfected and RSV-infected cells,
the predominant derivative (>80%) is the triphosphate,
which has an intracellular t 1/2
<2 hours.
Ribavirin monophosphate competitively inhibits
cellular inosine-5′-phosphate dehydrogenase and interferes
with the synthesis of GTP and thus nucleic acid
synthesis in general. Ribavirin triphosphate also competitively
inhibits the GTP-dependent 5′ capping of
viral messenger RNA and specifically influenza virus
transcriptase activity. Ribavirin appears to have multiple
sites of action, and some of these (e.g., inhibition
of GTP synthesis) may potentiate others (e.g., inhibition
of GTP-dependent enzymes). Ribavirin also may
enhance viral mutagenesis to an extent that some
viruses may be inhibited from effective replication, socalled
lethal mutagenesis (Hong and Cameron, 2002).
Emergence of viral resistance to ribavirin has not been documented
in most viruses but has been reported in Sindbis and HCV
(Young et al., 2003); it has been possible to select cells that do not
phosphorylate ribavirin to its active forms.
Absorption, Distribution, and Elimination. Ribavirin is actively
taken up by nucleoside transporters in the proximal small bowel;
oral bioavailability averages ~50% (Glue, 1999). Extensive accumulation
occurs in plasma, and steady state is reached by ~4 weeks.
Food increases plasma levels substantially (Glue, 1999). Following
single or multiple oral doses of 600 mg, peak plasma concentrations
average ~0.8 and 3.7 μg/mL, respectively. After intravenous doses of
1000 and 500 mg, plasma concentrations average ~24 and 17 μg/mL,
respectively. With aerosol administration, plasma levels increase
with the duration of exposure and range from 0.2 to 1.0 μg/mL after
5 days (Englund et al., 1990). Levels in respiratory secretions are
much higher but vary up to 1000-fold.
The apparent volume of distribution for ribavirin is large
(~10 L/kg) owing to its cellular uptake. Plasma protein binding is
negligible. The elimination of ribavirin is complex. The plasma t 1/2
increases to ~200-300 hours at steady state. Erythrocytes concentrate
ribavirin triphosphate; the drug exits red cells gradually, with
a t 1/2
of ~40 days. Hepatic metabolism and renal excretion of ribavirin
and its metabolites are the principal routes of elimination.
Hepatic metabolism involves deribosylation and hydrolysis to yield
a triazole carboxamide. Ribavirin clearance decreases by two-thirds
in those with advanced renal insufficiency (Cl cr
= 10-30 mL/minute);
the drug should be used cautiously in patients with creatinine clearances
of <50 mL/minute (Glue, 1999).
Untoward Effects. Aerosolized ribavirin may cause conjunctival irritation,
rash, transient wheezing, and occasional reversible deterioration
in pulmonary function. When used in conjunction with
mechanical ventilation, equipment modifications and frequent monitoring
are required to prevent plugging of ventilator valves and