- Toxicokinetics of the Ergot Alkaloids
- Future Research Directions
Toxicokinetics of the Ergot Alkaloids
The toxicokinetic aspects of tall fescue toxicants remain ill-defined. However, the pharmacokinetics of the drug bromocryptine (a synthetic ergot alkaloid) have been studied in a number of species (see review by Oliver, 1997) and indicate significant first-pass biotransformation of this alkaloid in the liver. Whether naturally occurring ergot alkaloids are similarly metabolized in ungulates remains to be determined. Naturally occurring ergot alkaloids have been detected in serum (Savary et al., 1990; Bony et al., 2001), urine and bile (Stuedemann et al., 1998; Schultz et al., 2006), ruminal and abomasal fluids (Westendorf et al., 1993; Craig et al., 1994), milk (Durix et al., 1999), and feces (Westendorf et al., 1993; Schultz et al., 2006) of sheep, cattle, and/or horses (see Chapters 16 and Chapter 17). When administered to ruminants, 50 to 60% of ergot and loline alkaloids were recovered in abomasal contents, while very little reached the ileum and only 5% were recovered in fecal collections, indicating extensive absorption from the gastrointestinal system (Piper and Moubarak, 1992; Westendorf et al., 1993). Stuedemann et al. (1998) provided data that supported results of Piper and Moubarak (1992) and Westendorf et al. (1993) concerning absorption of the alkaloids by the gastrointestinal system of ruminants. They reported that as much as 96% of the ergopeptine alkaloids (i.e., complex ergot alkaloids such as ergovaline and ergotamine) were excreted in the urine of cattle grazing endophyte infected (E+) pasture. Very little of the alkaloids consumed by these same animals was detected in the bile. This compared well with findings by Westendorf et al. (1993) that fecal ergot alkaloid recovery was only 6 to 7% when sheep received an E+ tall fescue seed diet for about 6 d (Westendorf et al., 1993). These findings would indicate that, in ruminants, gastrointestinal absorption of ergot alkaloids is in the range of 93 to 96% of the amount consumed. However, although both urine and feces were reported by Schultz et al. (2006) to be routes of ergot alkaloid excretion in horses, the amount of ergovaline, as a percentage of intake excreted in the feces, was substantially higher than that found by Westendorf et al. (1993) and Stuedemann et al. (1998) for sheep and cattle, respectively. In fact, the feces of exposed horses contained 35 to 40% of the total ergovaline consumed, indicating the feces were an important route of excretion for intact ergovaline in the horse. Furthermore, contrary to findings of Stuedemann et al. (1998) and Westendorf et al. (1993) for ruminants, ergovaline was not detected in the urine of geldings consuming the E+ tall fescue seed diet (Schultz et al., 2006). This would indicate that the remaining 60 to 65% of the ergovaline apparently were retained or metabolized to another form, perhaps lysergic acid.
Until relatively recently, it had been assumed that ergovaline, an ergopeptine, was the most important ergot alkaloid produced by the wild-type N. coenophialum endophyte in connection with the fescue toxicosis syndrome. However, recent gastrointestinal absorption research has suggested lysergic acid may play a more important role in fescue toxicosis than originally thought (Hill, 2004). Transport of ergot alkaloids across ruminal and omasal tissues was evaluated using parabiotic chambers. Lysergic acid was the only ergot alkaloid reported to be transported across these tissues, as measured by enzyme linked immunosorbent assay (ELISA) (Hill and Agee, 1994). From this observation, it was concluded that lysergic acid, not ergovaline, was the primary toxin causing fescue toxicosis. However, in a previous study (Hill et al., 2001), the authors reported that other ergot alkaloids (ergonovine, ergotamine, ergocryptine) were in fact transported across ruminal and omasal tissues, although not to the same extent as lysergic acid and lysergol. For both experiments, the ELISA method of Hill and Agee (1994), which is a nonspecific assay for total ergot alkaloid analysis, was used for quantification of transport. Findings by Schultz et al. (2006) suggested that lysergic acid was excreted by the horse in the feces in greater quantity than consumed (about 133% of total lysergic acid consumed), and more than 200% of the total lysergic acid intake was accounted for in the urine. These data were confirmed by high performance liquid chromatography (HPLC) (Craig et al., 1994; Jaussaud et al., 1998); thus, they were specific for the ergovaline discussed earlier and the lysergic acid discussed here. As mentioned, geldings in this study receiving the E+ tall fescue seed diet apparently retained 60 to 65% of the total ergovaline consumed. Currently, the site of transport of the ergot alkaloids in hindgut fermenters (i.e., equines) has yet to be determined. This led Schultz et al. (2006) to speculate that metabolism of ergovaline (or other ergot alkaloids not measured) to lysergic acid in the stomach, small intestine, hindgut, or the hepatic tissues may explain the excess levels of lysergic acid excreted by these animals in relation to intake.
The apparent differences in the metabolism and/or elimination of the ergot alkaloids discussed in the literature (Westendorf et al., 1993; Stuedemann et al., 1998; Hill et al., 2001; Schultz et al., 2006) may be due to a number of potential physiological differences among ungulates, including but not limited to diet selection and intakes, rate of digesta flow, hindgut versus foregut fermentation, affinity and capacity of absorption, excretory mechanisms, and hepatic and gastrointestinal tract epithelial metabolism. There is much research that still needs to be conducted concerning the effects of species, age, gender, and nutritional and physiological states on ergot alkaloid metabolism and elimination before a clear picture of the complete implications of, and solutions to, the intoxication can be realized fully.
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