Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

SELECTIVE TOXICITY
Table 10.2 Selective toxicity (continued)
Mechanism Parasite receptor Susceptible
parasite group
Cytochrome b
Inner mitochondrial
membrane (proton
ionophores)
Protozoa (Eimeria
and Hepatozoon)
Helminth (some
nematode and
cestode spp)
Enzyme Acetylcholinesterase Helminth
(nematodes),
arthropods
Chitin synthesis complex
Dihydrofolate reductase
(DHFR)
Dihydropteroate
synthase (DHPS)
Hypoxanthine-guanine
phosphoribosyl
transferase (HGPRT)
Arthropods
(especially
insects)
Protozoa
Antiparasitic
agents
Decoquinate
Niclosamide,
disophenol,
dichlorophen
Chlorpyrifos,
diazinon, fenthion,
malathion,
carbaryl, propoxur
Lufenuron
Trimethoprim,
pyrimethamine
Antiparasitic action
Antagonist
Potent inhibitor of
Eimeria NADH or
succinate-induced
mitochondrial
respiration
Antagonist
Uncouple oxidative
phosphorylation
Antagonist
Inhibition of OP and
carbamate
hydrolysis
Antagonist
Inhibition of chitin
synthesis and
cuticle formation
(not via inhibition of
chitin synthase)
Antagonist
Inhibits conversion of
dihydrofolate to
tetrahydrofolate,
blocking 1-carbon
transfers involved
in purine,
pyrimidine and
methionine
synthesis as well
as metabolism of
serine, glycine,
histidine and
glutamate
Protozoa Sulfonamides Antagonist
Inhibits synthesis of
dihydropteroate
from p-amino
benzoic acid
(PABA) and 6-
hydroxymethyl-
7,8-pterin
pyrophosphate
Protozoa (especially
trypanosomatids)
Allopurinol
Agonist (subversive)
Allopurinol is
converted to
the inosine
monophosphate
(IMP) analog,
thence via
sequential
reactions to the
ATP derivative and
finally incorporated
into RNA where
function is blocked
Comments on
selective toxicity*
PK: poor oral
bioavailability
PD: no effect on in vitro
mammalian
mitochondrial
respiration
PK: low oral
bioavailability; high
protein binding
PD: no selectivity
PK: dermal barrier;
rapid metabolic
inactivation by host
PD: no selectivity
PK: low selectivity
PD: chitin not present in
mammals
PK: low selectivity: high
bioavailability
PD: increased lipid
solubility of
pyrimethamine
associated with
2000-fold greater
affinity for protozoal
DHFR than
mammalian DHFR.
Mammalian DHFR
upregulated in
response to inhibition
PK: low selectivity: high
bioavailability
PD: mammals do not
synthesize folate and
have no DHPS
PK: rapidly metabolized
by xanthine oxidase
to oxypurinol which is
not a substrate for
HGPRT
PD: mammalian
HGPRT has low
affinity for allopurinol
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