• 1. McConnico RS, Morgan TW, Williams CC, et al. Pathophysiologic effects of phenylbutazone on the right dorsal colon in horses. Am J Vet Res 2008;69:14961505.

    • Search Google Scholar
    • Export Citation
  • 2. Marshall JF, Blikslager AT. The effect of nonsteroidal anti-inflammatory drugs on the equine intestine. Equine Vet J Suppl 2011;39:140144.

    • Search Google Scholar
    • Export Citation
  • 3. Sykes BW, Hewetson M, Hepburn RJ, et al. European College of Equine Internal Medicine consensus statement—equine gastric ulcer syndrome in adult horses. J Vet Intern Med 2015;29:12881299.

    • Search Google Scholar
    • Export Citation
  • 4. Dollery CT. Misoprostol. In: Dollery CT, ed. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone, 1999;193–197.

  • 5. Blikslager AT. Misoprostol: is it safety or lack of understanding that prevents its more frequent usage? Equine Vet J 2013;45:8.

  • 6. Collins LG, Tyler DE. Experimentally induced phenylbutazone toxicosis in ponies: description of the syndrome and its prevention with synthetic prostaglandin E2. Am J Vet Res 1985;46:16051615.

    • Search Google Scholar
    • Export Citation
  • 7. Varley G, Bowen IM, Habershon-Butcher JL, et al. Misoprostol is superior to combined omeprazole, sucralfate for the treatment of equine gastric glandular disease. Equine Vet J 2019;51:575580.

    • Search Google Scholar
    • Export Citation
  • 8. Martin EM, Messenger KM, Sheats MK, et al. Misoprostol inhibits lipopolysaccharide-induced pro-inflammatory cytokine production by equine leukocytes. Front Vet Sci 2017;4:160.

    • Search Google Scholar
    • Export Citation
  • 9. Martin EM, Till RL, Sheats MK, et al. Misoprostol inhibits equine neutrophil adhesion, migration, and respiratory burst in an in vitro model of inflammation. Front Vet Sci 2017;4:159.

    • Search Google Scholar
    • Export Citation
  • 10. Martin EM, Schirmer JM, Jones SL, et al. Pharmacokinetics and ex vivo anti-inflammatory effects of oral misoprostol in horses. Equine Vet J 2019;51:415421.

    • Search Google Scholar
    • Export Citation
  • 11. Gobejishvili L, Ghare S, Khan R, et al. Misoprostol modulates cytokine expression through a cAMP pathway: potential therapeutic implication for liver disease. Clin Immunol 2015;161:291299.

    • Search Google Scholar
    • Export Citation
  • 12. Cooper DL, Murrell DE, Conder CM, et al. Exacerbation of celecoxib-induced renal injury by concomitant administration of misoprostol in rats. PLoS One 2014;9:e89087.

    • Search Google Scholar
    • Export Citation
  • 13. Meja KK, Barnes PJ, Giembycz MA. Characterization of the prostanoid receptor(s) on human blood monocytes at which prostaglandin E2 inhibits lipopolysaccharide-induced tumour necrosis factor-α generation. Br J Pharmacol 1997;122:149157.

    • Search Google Scholar
    • Export Citation
  • 14. Widomski D, Fretland D, Gasiecki A, et al. The prostaglandin analogs, misoprostol and SC-46275, potently inhibit cytokine release from activated human monocytes. Immunopharmacol Immunotoxicol 1997;19:165174.

    • Search Google Scholar
    • Export Citation
  • 15. Smallwood JI, Malawista SE. Misoprostol stimulates cAMP generation in human leukocytes: synergy with colchicine suggests a new potential for established drugs. Am J Ther 1995;2:725729.

    • Search Google Scholar
    • Export Citation
  • 16. Chilcoat CD, Rowlingson KA, Jones SL. The effects of cAMP modulation upon the adhesion and respiratory burst activity of immune complex-stimulated equine neutrophils. Vet Immunol Immunopathol 2002;88:6577.

    • Search Google Scholar
    • Export Citation
  • 17. Davies NM, Longstreth J, Jamali F. Misoprostol therapeutics revisited. Pharmacotherapy 2001;21:6073.

  • 18. Echeverria KO, Lascola KM, Giguère S, et al. Effect of feeding on the pharmacokinetics of oral minocycline in healthy adult horses. J Vet Pharmacol Ther 2018;41:e53e56.

    • Search Google Scholar
    • Export Citation
  • 19. Davis JL, Salmon JH, Papich MG. Pharmacokinetics and tissue distribution of doxycycline after oral administration of single and multiple doses in horses. Am J Vet Res 2006;67:310316.

    • Search Google Scholar
    • Export Citation
  • 20. Bouckaert S, Voorspoels J, Vendenbossche G, et al. Effect of drug formulation and feeding on the pharmacokinetics of orally administered quindine in the horse. J Vet Pharmacol Ther 1994;17:275278.

    • Search Google Scholar
    • Export Citation
  • 21. Sykes BW, Underwood C, McGowen CM, et al. The effect of feeding on the pharmacokinetic variables of two commercially available formulations of omeprazole. J Vet Pharmacol Ther 2015;38:500503.

    • Search Google Scholar
    • Export Citation
  • 22. van Duijkeren E, Vulton AG, Sloet van Oldruitenborgh-Oosterbaan MM, et al. Pharmacokinetics of trimethoprim/sulphachlorpyridazine in horses after oral, nasogastric and intravenous administration. J Vet Pharmacol Ther 1995;18:4753.

    • Search Google Scholar
    • Export Citation
  • 23. McKellar QA, Horspool LJ. Stability of penicillin G, ampicillin, amikacin, and oxytetracycline and their interactions with food in in vitro simulated equine gastrointestinal contents. Res Vet Sci 1995;58:227231.

    • Search Google Scholar
    • Export Citation
  • 24. Welsh JC, Lees P, Stodulski G, et al. Influence of feeding schedule on the absorption of orally administered flunixin in the horse. Equine Vet J Suppl 1992;11:6265.

    • Search Google Scholar
    • Export Citation
  • 25. Alvinerie M, Sutra JF, Cabezas I, et al. Enhanced plasma availability of moxidectin in fasted horses. J Equine Vet Sci 2000;20:575578.

    • Search Google Scholar
    • Export Citation
  • 26. Britzi M, Gross M, Lavy E, et al. Bioavailability and pharmacokinetics of metronidazole in fed and fasted horses. J Vet Pharmacol Ther 2010;33:511514.

    • Search Google Scholar
    • Export Citation
  • 27. Baggot JD, Love DN, Stewart J, et al. Bioavailability and disposition kinetics of amoxicillin in neonatal foals. Equine Vet J 1988;20:125127.

    • Search Google Scholar
    • Export Citation
  • 28. Meckstroth KR, Whitaker AK, Bertisch S, et al. Misoprostol administered by epithelial routes: drug absorption and uterine response. Obstet Gynecol 2006;108:582590.

    • Search Google Scholar
    • Export Citation
  • 29. Tang OS, Schweer H, Seyberth HW, et al. Pharmacokinetics of different routes of administration of misoprostol. Hum Reprod 2002;17:332336.

    • Search Google Scholar
    • Export Citation
  • 30. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmacokinetic profiles, effects on the uterus, and side effects. Int J Gynaecol Obstet 2007;99:S160S167.

    • Search Google Scholar
    • Export Citation
  • 31. Khan RU, El-Refaey H, Sharma S, et al. Oral, rectal, and vaginal pharmacokinetics of misoprostol. Obstet Gynecol 2004;103:866870.

  • 32. Zieman M, Fong SK, Benowitz NL, et al. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:8892.

    • Search Google Scholar
    • Export Citation
  • 33. Aronsson A, Fiala C, Stephansson O, et al. Pharmacokinetic profiles up to 12 hours after administration of vaginal, sublingual, and slow release oral misoprostol. Hum Reprod 2007;22:19121918.

    • Search Google Scholar
    • Export Citation
  • 34. Foote EF, Lee DR, Karim A, et al. Disposition of misoprostol and its active metabolite in patients with normal and impaired renal function. J Clin Pharmacol 1995;35:384389.

    • Search Google Scholar
    • Export Citation
  • 35. Fiala C, Aronsson A, Granath F, et al. Pharmacokinetics of a novel oral slow-release form of misoprostol. Hum Reprod 2005;20:34143418.

    • Search Google Scholar
    • Export Citation
  • 36. FDA. Cytotec misoprostol tablets. 2009. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2009/019268s041lbl.pdf. Accessed Apr 14, 2019.

    • Search Google Scholar
    • Export Citation
  • 37. Vijaya Bharathi D, Jagadeesh B, Hotha KK, et al. Development and validation of highly sensitive method for determination of misoprostol free acid in human plasma by liquid chromatography-electrospray ionization tandem mass spectrometry: application to a clinical pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2011;879:28272833.

    • Search Google Scholar
    • Export Citation
  • 38. Toothaker RD, Welling PG. The effect of food on drug bioavailability. Annu Rev Pharmacol Toxicol 1980;20:173199.

  • 39. Maxwell L. Horse of a different color: peculiarities of equine pharmacology. In: Cole C, Bentz B, Maxwell L, eds. Equine pharmacology. Hoboken, NJ: John Wiley & Sons Inc, 2015:315.

    • Search Google Scholar
    • Export Citation
  • 40. Tang OS, Schweer H, Lee SWH, et al. Pharmacokinetics of repeated doses of misoprostol. Hum Reprod 2009;24:18621869.

  • 41. Steinman A, Gips M, Lavy E, et al. Pharmacokinetics of metronidazole in horses after intravenous, rectal and oral administration. J Vet Pharmacol Ther 2000;23:353357.

    • Search Google Scholar
    • Export Citation
  • 42. Baggot JD. The concept of bioavailability and applications to veterinary dosage forms. In: Baggot JD, ed. Physiologic basis of veterinary clinical pharmacology. Oxford: Blackwell Science Ltd, 2001;5591.

    • Search Google Scholar
    • Export Citation
  • 43. De Boer AG, De Leede LGJ, Breimer DD. Drug absorption by sublingual and rectal routes. Br J Anaesth 1984;56:6982.

  • 44. Steel CM, Bolton JR, Preechagoon Y, et al. Unreliable rectal absorption of cisapride in horses. Equine Vet J 1999;31:8284.

  • 45. Christensen JM, Limsakun T, Smith BB, et al. Pharmacokinetics and pharmacodynamics of antiulcer agents in llama. J Vet Pharmacol Ther 2001;24:2333.

    • Search Google Scholar
    • Export Citation
  • 46. Tunçalp Ö, Hofmeyr GJ, Gülmezoglu AM. Prostaglandins for preventing postpartum haemorrhage. Cochrane Database Syst Rev 2012;8:CD000494.

    • Search Google Scholar
    • Export Citation
  • 47. Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med 2001;344:3847.

  • 48. Jacobson CC, Sertich PL, McDonnell SM. Mid-gestation pregnancy is not disrupted by a 5-day gastrointestinal mucosal cytoprotectant oral regimen of misoprostol. Equine Vet J 2013;45:9193.

    • Search Google Scholar
    • Export Citation
  • 49. Sangiah S, MacAllister CC, Amouzadeh HR. Effects of misoprostol and omeprazole on basal gastric pH and free acid content in horses. Res Vet Sci 1989;47:350354.

    • Search Google Scholar
    • Export Citation
  • 50. Brayden DJ, Maher S, Bahar B, et al. Sodium caprate-induced increases in intestinal permeability and epithelial damage are prevented by misoprostol. Eur J Pharm Biopharm 2015;94:194206.

    • Search Google Scholar
    • Export Citation
  • 51. Blikslager AT, Pell SM, Young KM. PGE2 triggers recovery of transmucosal resistance via EP receptor cross talk in porcine ischemia-injured ileum. Am J Physiol Gastrointest Liver Physiol 2001;281:G375G381.

    • Search Google Scholar
    • Export Citation
  • 52. Dajani EZ, Nissen CH. Gastrointestinal cytoprotective effects of misoprostol. Clinical efficacy overview. Dig Dis Sci 1985;30:194S200S.

    • Search Google Scholar
    • Export Citation

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Single-dose pharmacokinetics of orally and rectally administered misoprostol in adult horses

Christine T. Lopp DVM1, Annette M. McCoy DVM, PhD1, Dawn Boothe DVM, PhD2, David J. Schaeffer PhD1, and Kara Lascola DVM, MS2
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  • 1 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802
  • | 2 2Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL 36849

Abstract

OBJECTIVE

To characterize the pharmacokinetics of a clinically relevant dose of misoprostol administered PO or per rectum (PR) to horses.

ANIMALS

8 healthy adult horses.

PROCEDURES

In a randomized 3-way crossover design, horses received a single dose of misoprostol (5 μg/kg) administered PO (with horses fed and unfed) and PR, with a minimum 3-week washout period separating the experimental conditions. Blood samples were obtained before and at various points after drug administration (total, 24 hours), and plasma concentrations of misoprostol free acid were measured.

RESULTS

Mean maximum plasma concentration of misoprostol was significantly higher in the PR condition (mean ± SD, 967 ± 492 pg/mL) and unfed PO condition (655 ± 259 pg/mL) than in the fed PO condition (352 ± 109 pg/mL). Mean area under the concentration-versus-time curve was significantly lower in the PR condition (219 ± 131 pg•h/mL) than in the unfed (1,072 ± 360 pg•h/mL) and fed (518 ± 301 pg•h/mL) PO conditions. Mean time to maximum concentration was ≤ 30 minutes for all conditions. Mean disappearance half-life was shortest in the PR condition (21 ± 29 minutes), compared with values for the unfed (170 ± 129 minutes) and fed (119 ± 51 minutes) PO conditions. No adverse effects were noted.

CONCLUSIONS AND CLINICAL RELEVANCE

Misoprostol was rapidly absorbed and eliminated regardless of whether administered PO or PR to horses. Rectal administration may be a viable alternative for horses that cannot receive misoprostol PO, but this route may require more frequent administration to maintain therapeutic drug concentrations.

Abstract

OBJECTIVE

To characterize the pharmacokinetics of a clinically relevant dose of misoprostol administered PO or per rectum (PR) to horses.

ANIMALS

8 healthy adult horses.

PROCEDURES

In a randomized 3-way crossover design, horses received a single dose of misoprostol (5 μg/kg) administered PO (with horses fed and unfed) and PR, with a minimum 3-week washout period separating the experimental conditions. Blood samples were obtained before and at various points after drug administration (total, 24 hours), and plasma concentrations of misoprostol free acid were measured.

RESULTS

Mean maximum plasma concentration of misoprostol was significantly higher in the PR condition (mean ± SD, 967 ± 492 pg/mL) and unfed PO condition (655 ± 259 pg/mL) than in the fed PO condition (352 ± 109 pg/mL). Mean area under the concentration-versus-time curve was significantly lower in the PR condition (219 ± 131 pg•h/mL) than in the unfed (1,072 ± 360 pg•h/mL) and fed (518 ± 301 pg•h/mL) PO conditions. Mean time to maximum concentration was ≤ 30 minutes for all conditions. Mean disappearance half-life was shortest in the PR condition (21 ± 29 minutes), compared with values for the unfed (170 ± 129 minutes) and fed (119 ± 51 minutes) PO conditions. No adverse effects were noted.

CONCLUSIONS AND CLINICAL RELEVANCE

Misoprostol was rapidly absorbed and eliminated regardless of whether administered PO or PR to horses. Rectal administration may be a viable alternative for horses that cannot receive misoprostol PO, but this route may require more frequent administration to maintain therapeutic drug concentrations.

Contributor Notes

Dr. Lopp's present address is Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762.

Address correspondence to Dr. Lascola (km10068@auburn.edu).