Page 1038 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

970 SECTION | XIV Poisonous Plants

VetBooks.ir kidneys and the major route of excretion is biliary following apparent among rodents: compared with mice, rats have a
Interspecies pharmacokinetic differences are also
glucuronidation and/or sulfation and/or complexation with
much lower volume of distribution and a substantially
iron (Gadelha et al., 2014). Small amounts are excreted in
urine. In rats, elimination is biphasic. Repeated daily PO lower AUC for a given dose. The volume of distribution
dosing is associated with an approximate doubling of the in mice is much higher than 1 L/kg, implying substantial
apparent elimination half-life (to 101.89 h) compared with tissue sequestration (consistent with accumulation in liver
single dosing and plasmatic/whole body accumulation is and kidney). Mice also eliminate gossypol approximately
apparent (Othman and Abou-Donia, 1988). This is consis- seven times faster compared with rats. These pharmacoki-
tent with gossypol usually behaving as a cumulative toxin. netic differences may contribute to the resistance of mice
Studies on individuals isomers have reported conflicting (compared with rats) to the contraceptive action of
results: one study demonstrated no effect of isomeric form (1/ 2 )-gossypol (Abou-Donia et al., 1989).
on pharmacokinetic parameters in rats (Othman and Abou- Excretion of gossypol in milk is usually regarded as
Donia, 1988). However, a separate single IV dose study in being extremely low (negligible). However, gossypol was
rats demonstrated that the terminal half-life of the (1)iso- detected in milk following 30 and 60 days of feeding of
mer was approximately double that of the (2)isomer (Chen whole cotton seeds containing 385.43 611.2 mg/kg of
et al., 1987). Single IV dose studies in dogs demonstrated free gossypol (but not cottonseed meal containing
that the elimination and volume of distribution of (1)-gos- 91.15 117.32 mg/kg free gossypol) to dairy cattle (Wang
sypol were five and six times those of (2)-gossypol whereas et al., 2012).
total body clearance and the AUC of the two enantiomers
were similar (Wu et al., 1986). In humans the elimination SUSCEPTIBILITY TO TOXICITY
half-life of (1)-gossypol was 29 times that of (2)-gossypol
(Wu et al., 1986). In mid-lactation Brown Swiss dairy cows, Gossypol toxicity has been reported in poultry, pigs, dogs,
repeated daily PO dosing for 7 days was associated with a cats, guinea pigs, sheep, goats, cattle, rabbits, rodents,
terminal elimination half-life of 40 68 h (Lin et al., monkeys, fish, and humans (Table 68.2). As a rule of
1991). thumb, all species should be regarded as being susceptible

TABLE 68.2 Dietary Gossypol and Disease

Species Dietary Level Effects Reference
Horse 115 ppm No adverse effects noted Potter G.D. (1981) Use of cottonseed
(yearling) meal in rations for young horses.
Feedstuffs (53): 29
Horse (foal) 348 ppm No adverse effects noted McCall M.A. (1982) Cottonseed
Meal Supplement in Weanling and
Suckling Foal Diets. Texas A&M
University, College Station, TX. MS
thesis
Cattle 400 mg/kg BW/day Centrilobular hepatic necrosis, Velasquez-Pereira J., Risco C.A.,
(calves, Free gossypol cardiocyte vacuolation McDowell L.R., et al. (1999) Long-
dairy) term effects of feeding gossypol and
vitamin E to dairy calves. J Dairy Sci.
82: 1240 1251
Cattle 250 380 ppm Fed during first 10 weeks of age. Holmberg C.A., Weaver L.D.,
(calves, High mortality; developed ascites, Guterbock W.M., et al. (1988)
dairy) diarrhea, weakness after consuming Pathological and toxicological
for 70 180 days studies of calves fed a high
concentration cottonseed meal diet.
Vet Pathol 25: 147 153
Cattle (adult, 6.2 mg/kg BW/day No adverse effects Lindsey T.O., Hawkins G.E., Guthrie
dairy) Free gossypol L.D. (1980) Physiological responses
of lactating cows to gossypol from
8.8 mg/kg BW/day Fed for 100 days.
cottonseed meal rations. J Dairy Sci
63: 562 573
(Continued )