title: Toxicokinetic profile of swainsonine following exposure to locoweed (Oxytropis sericea) in naïve and previously exposed sheep.
abstract: OBJECTIVE
  To determine the toxicokinetic profiles of swainsonine (SW) in sheep previously (subacute) and not previously (acute) exposed to locoweed.
  
  
  METHODS
  Twenty-nine wethers were stratified by bodyweight (BW; 68.0 (SE 7.6) kg) and randomly assigned to one of six treatments. Treatments were: 0 (n=5), 0.4 (n=5), and 1.6 (n=5) mg SW/kg BW for Trial 1, and 0 (n=4), 0.2 (n=5), and 0.8 (n=5) mg SW/kg BW for Trial 2. Acute exposure in both trials included adaptation to blue grama (Bouteloua gracilis) hay for 14 days and no previous exposure to locoweed (i.e. SW), followed by administration of a single oral dose of SW prepared from an extract of locoweed, in the doses described above. Subacute exposure comprised ingestion of a blue grama and locoweed (428 microg SW/g locoweed) diet for 21 days in Trial 1 and 28 days in Trial 2, followed by removal from locoweed for 5 days, then an oral dose of SW, as above. Quantities of locoweed fed in the diet were adjusted to achieve the dose rates specified for each treatment. Blood samples were collected via jugular venepuncture twice daily for 3 days prior to initial exposure to SW and then every 7 days for the duration of the trials, to monitor serum alkaline phosphatase (Alk-P) and aspartate aminotransferase (AST) activities. For intensive sampling periods, SW was administered immediately following blood sampling at 0 h, and blood samples were collected at hourly intervals from 0-12 h, 3-h intervals from 15-24 h, 6-h intervals from 30-48 h, and 12-h intervals from 60-168 h. Concentrations of SW in serum and locoweed extract were determined using the alpha-mannosidase inhibition assay (detection limit=25 ng/ml). Rates of absorption and elimination of SW from serum were calculated for each animal, using exponential curve fits of the concentration of SW in serum concentration vs time plots.
  
  
  RESULTS
  In both trials, SW was detected in serum in all animals exposed to locoweed. Elevated (p<0.05) serum Alk-P and AST activities indicated that subclinical SW intoxication was induced during the subacute exposure phase. Calculated rates of elimination were faster (p<0.001) for the 1.6 vs 0.4 (Trial 1) and 0.8 vs 0.2 (Trial 2) mg SW/kg BW doses. Rates of elimination indicated that, in both trials, SW was removed from serum faster (p<0.06) following acute exposure than subacute exposure. Higher exposure rates to SW resulted in higher concentrations of SW in serum within a trial.
  
  
  CONCLUSIONS
  Multiple compartments were involved in the kinetics of SW, and dose and previous exposure altered the toxicokinetics of SW. CLININCAL RELEVANCE: Should the true elimination half-life prove to be as high or higher than the 95 h demonstrated for the treatment using 0.4 mg SW/kg BW in Trial 1, then withdrawal periods for clearing SW from sheep should be >40 days (assuming 10 half-lives to clear the compound).
authors.affiliation: New Mexico State University, Las Cruces NM 88003, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Ashley
authors.forename: M
authors.initials: M
authors.lastname: Custis
authors.forename: R
authors.initials: R
authors.lastname: Ashley
authors.forename: J R
authors.initials: JR
authors.lastname: Strickland
mesh_terms: D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity; D007408:Intestinal Absorption; D008099:Liver / Q000201:enzymology*; D008297:Male; D008657:Metabolic Clearance Rate; D033021:Oxytropis / Q000737:chemistry; D010939:Plant Poisoning / Q000378:metabolism / Q000662:veterinary*; D011897:Random Allocation; D012756:Sheep; D012757:Sheep Diseases / Q000378:metabolism*; D017026:Swainsonine / Q000493:pharmacokinetics* / Q000633:toxicity; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase; D017026:Swainsonine