Page 624 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Anticoagulant Chapter | 46 589

VetBooks.ir Precursor proteins Factors II, VII, IX, X is biphasic, with a rapid phase of 5 days, then a prolonged
−
O
O
phase of 100 days in Japanese quail (Huckle et al., 1989a,b).
O−
O−
Alteration of parental behavior was speculated to be a
C
C C cause of 54% lethality in offspring in the face of 40%
CH 2
O CH O lethality of lactating female albino rats dosed with couma-
Glutamyl
residues CH γ -Carboxy- tetralyl (Marchini and Turillazzi, 1978). However, pas-
2 Vitamin K -dependent CH 2 glutamyl
1
carboxylation carboxylase residues sage into milk is an alternative theory.
CO 2 O 2
Elimination
Vitamin K 1 The different chemical structures give different elimina-
O 2 epoxidase tion kinetics for the various anticoagulant rodenticides.
Vitamin K hydroquinone Vitamin K 1 Elimination kinetics is estimated from human or animal
1
epoxide
Vitamin K 1
DT-diaphorase epoxide reductase clinical cases in many instances. Such cases are presented
for the 4-hydroxycoumarins warfarin, brodifacoum, difena-
S S Vitamin K 1 coum, bromadiolone, difethialone, and chlorophacinone.
SH SH
SH SH S S Warfarin has a terminal half-life of 5.6 1 0.7 h, with a
mono-exponential decay (Breckenridge et al., 1985).
FIGURE 46.1 Liver metabolism of vitamin K. The dithiol-dependent Brodifacoum and difenacoum have a bi-exponential
vitamin K 1 epoxide reduction and vitamin K 1 (Phylloquinone) reduction decay of 60 6 1.9 and 83 6 10 h, respectively, in rabbits
are the metabolic steps inhibited by anticoagulant rodenticides. (Breckenridge et al., 1985). An estimated median half-life
of brodifacoum elimination in dogs has been estimated to
TOXICITY be 2.4 days (Robben et al., 1998), although the data may
reflect only the first elimination phase. Plasma half-life
TOXICOKINETICS for brodifacoum was reported to initially be 0.75 days,
with a terminal half-life of 24.3 days in a patient with
Bioavailability
hematuria requiring 4 months of phytonadione treatment.
Most anticoagulant rodenticide toxicoses occur after oral A 41-year-old man had a terminal half-life of 11.7
exposure. However, a diphacinone-induced coagulopathy days for difenacoum after covert administration of an
has been reported after dermal exposure to a liquid prepa- unknown amount of the drug (McCarthy et al., 1997). A
ration (Spiller et al., 2003), and an unusual case is second individual had a peak serum concentration of
reported after exposure to brodifacoum after transplanta- 600 ng/mL (Butcher et al., 1992).
tion of multiple organs (Ornstein et al., 1999). A peak serum concentration of 440 ug/L, then an elim-
The oral bioavailability of warfarin, chlorophacinone, ination half-life of 140 h, was reported in a 55-year-old
and bromadiolone were estimated at 79%, 92%, and 88%, man who ate an unknown amount of bromadiolone
respectively, in sheep. These anticoagulants degraded by (Grobosch et al., 2006). Elimination half-lives of 2.2 and
about 15% over 24 h in rumen extracts. The bioavailabil- 3.2 days have been reported in 2 dogs with difethialone
ity of warfarin is influenced by dietary protein (Barber exposure, respectively (Robben et al., 1998). A half-life
and Colvin, 1980). of 5 days is reported in sheep dosed with pindone
(Robinson et al., 2005).

Distribution
Sixty percent of 14 C-labeled diphacinone is eliminated in Duration
feces and 10% in urine over 4 days in mice and 8 days in Despite reported elimination half-lives, the duration of the
rats (Yu et al., 1982). Tissue distribution indicated that anticoagulant effect provides an indication of the clini-
liver had the most 14 C activity, with the lowest amounts cally relevant treatment times. Brodifacoum and difena-
in brain, muscle, blood, and fat (Yu et al., 1982). The dis- coum cases seem to have the longest duration of
position and pharmacodynamic properties of brodifacoum anticoagulant effect in animals and humans.
have also been characterized in rats (Bachmann, Sullivan, Rabbits are anticoagulated 6 weeks after oral exposure
1983). Similarly, 30% of 14 C-labeled fluocoumafen is to 1 mg/kg body wt. brodifacoum (Park and Leck, 1982).
eliminated in feces and less than 3% in urine within Although clotting times were prolonged for 7 months
3 days in rats (Huckle et al., 1988). About 60% of 14 C after a person’s exposure to an unknown amount of dife-
fluocoumafen is liable to beta-glucuronidase, and most nacoum (McCarthy et al., 1997), elevated concentrations
radioactivity is found unchanged in the liver. Elimination of vitamin K 1 2,3-epoxide were detected for 18 months