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

Like all available antiretroviral drugs, nucleoside
and nucleotide reverse transcriptase inhibitors prevent
infection of susceptible cells but do not eradicate the
virus from cells that already harbor integrated proviral
DNA. Nucleoside and nucleotide analogs must enter
cells and undergo phosphorylation to generate synthetic
substrates for the enzyme (Table 59–2). The fully phosphorylated
analogs block replication of the viral
genome both by competitively inhibiting incorporation
of native nucleotides and by terminating elongation of
nascent proviral DNA because they lack a 3′-hydroxyl
group (Dudley, 1995).
All but one of the drugs in this class are nucleosides that must be
triphosphorylated at the 5′-hydroxyl to exert activity. The sole exception,
tenofovir, is a nucleotide monophosphate analog that requires two
additional phosphates to acquire full activity. These compounds inhibit
both HIV-1 and HIV-2, and several have broad-spectrum activity against
other human and animal retroviruses; emtricitabine, lamivudine, and
tenofovir are active against hepatitis B virus (HBV), and tenofovir also
has activity against herpesviruses (Chapter 58; De Clercq, 2003).
The selective toxicity of these drugs depends on
their ability to inhibit the HIV reverse transcriptase
without inhibiting host cell DNA polymerases.
ZDV
Thymidine
Thymidine
kinase
Thymidylate
kinase
NDP
kinase
d4T
ZDV-MP d4T-MP ddC-MP
ZDV-DP
ZDV-TP
d4T-DP
d4T-TP
ddC
ddC-DP
ddC-TP
Deoxycytidine
kinase
NDP kinase
Although the intracellular triphosphates for all these
drugs have low affinity for human DNA polymeraseα
and -β, some are capable of inhibiting human DNA
polymerase-γ, which is the mitochondrial enzyme. As
a result, the important toxicities common to this class
of drugs result in part from the inhibition of mitochondrial
DNA synthesis (Lee et al., 2003). These toxicities
include anemia, granulocytopenia, myopathy,
peripheral neuropathy, and pancreatitis. Lactic acidosis
with or without hepatomegaly and hepatic steatosis
is a rare but potentially fatal complication seen
with stavudine, zidovudine, and didanosine; it is probably
not associated independently with the other
drugs (Tripuraneni et al., 2004). Phosphorylated
emtricitabine, lamivudine, and tenofovir have low
affinity for DNA polymerase-γ and are largely devoid
of mitochondrial toxicity.
The chemical structures of nucleoside and
nucleotide reverse transcriptase inhibitors approved
for treating HIV infection are shown in Figure 59–2;
their pharmacokinetic properties are summarized in
Table 59–2. Phosphorylation pathways for these eight
drugs are summarized in Figure 59–3. Most nucleoside
and nucleotide reverse transcriptase inhibitors are
Cytidine Guanosine Adenosine
CMP/dCMP
kinase
FTC/3TC
FTC/3TC-MP
FTC/3TC-DP
3TC-TP
ABC
Adenosine
phosphotransferase
ABC-MP
Cytosolic
enzyme
CBV-MP
Kinase
CBV-DP
Kinase
ddl
5’ Nucleotidase/
IMP phosphotransferase
ddl-MP
Adenylsuccinate
synthase
& lyase
ddA-MP
Adenylate kinase/
PRPP synthase
ddA-DP
Creatine kinase/
PRPP synthase
Tenofovir DF
Diester
hydrolysis
Tenofovir
AMP
kinase
TFV-MP
NDP
kinase
TFV-DP
1631
CHAPTER 59
ANTIRETROVIRAL AGENTS AND TREATMENT OF HIV INFECTION
FTC-TP
CBV-TP
ddA-TP
Figure 59–3. Intracellular activation of nucleoside analog reverse transcriptase inhibitors. Drugs and phosphorylated anabolites are
abbreviated; the enzymes responsible for each conversion are spelled out. The active antiretroviral anabolite for each drug is shown
in the blue box. Key: ZDV, zidovudine; d4T, stavudine; ddC, dideoxycytidine; FTC, emtricitabine; 3TC, lamivudine; ABC, abacavir;
ddI, didanosine; DF, disoproxil fumarate; MP, monophosphate; DP, diphosphate; TP, triphosphate; AMP, adenosine mono phosphate;
CMP, cytidine monophosphate; dCMP, deoxycytidine monophosphate; IMP, inosine 5′-monophosphate; PRPP, phosphoribosyl
pyrophosphate; NDP, nucleoside diphosphate. (Adapted with permission from Khoo et al., 2002. Copyright © Elsevier.)