• 1. Langlois DK, Smedley RC, Schall WD, et al. Acquired proximal renal tubular dysfunction in 9 Labrador Retrievers with copper-associated hepatitis (2006–2012). J Vet Intern Med 2013; 27: 491499.

    • Search Google Scholar
    • Export Citation
  • 2. Brewer GJ, Askari F, Dick RB, et al. Treatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper by tetrathiomolybdate and a comparison with trientine. Transl Res 2009; 154: 7077.

    • Search Google Scholar
    • Export Citation
  • 3. Gooneratne SR, Howell JM, Gawthorne JM. Intravenous administration of thiomolybdate for the prevention and treatment of chronic copper poisoning in sheep. Br J Nutr 1981; 46: 457467.

    • Search Google Scholar
    • Export Citation
  • 4. Smedley R, Mullaney T, Rumbeiha W. Copper-associated hepatitis in Labrador Retrievers. Vet Pathol 2009; 46: 484490.

  • 5. Walshe JM. Penicillamine, a new oral therapy for Wilson's disease. Am J Med 1956; 21: 487495.

  • 6. Dick AT, Bull LB. Some preliminary observations on the effect of molybdenum on copper metabolism in herbivorous animals. Aust Vet J 1945; 21: 7072.

    • Search Google Scholar
    • Export Citation
  • 7. Hardy RM, Stevens JB, Stowe CM. Chronic progressive hepatitis in Bedlington Terriers associated with elevated copper concentrations. Minn Vet 1975; 15: 1324.

    • Search Google Scholar
    • Export Citation
  • 8. Mandigers PJJ, Van Den Ingh TSGAM, Bode P, et al. Improvement in liver pathology after 4 months of d-penicillamine in 5 Doberman Pinschers with subclinical hepatitis. J Vet Intern Med 2005; 19: 4043.

    • Search Google Scholar
    • Export Citation
  • 9. Robertson HM. Inherited copper toxicosis in Bedlington Terriers. Aust Vet J 1983; 60: 235238.

  • 10. Fieten H, Dirksen K, Van Den Ingh TSGAM, et al. d-penicillamine treatment of copper-associated hepatitis in Labrador Retrievers. Vet J 2013; 196: 522527.

    • Search Google Scholar
    • Export Citation
  • 11. Hoffmann G. Copper-associated liver diseases. Vet Clin North Am Small Anim Pract 2009; 39: 489511.

  • 12. Langlois DK, Lehner AF, Buchweitz JP, et al. Pharmacokinetics and relative bioavailability of d-penicillamine in fasted and nonfasted dogs. J Vet Intern Med 2013; 27: 10711076.

    • Search Google Scholar
    • Export Citation
  • 13. Suzuki KT. Selective removal of copper accumulating in a form bound to metallothionein in the liver of LEC rats by tetrathiomolybdate. J Trace Elem Exp Med 1997; 10: 101109.

    • Search Google Scholar
    • Export Citation
  • 14. Brewer GJ, Dick RD, Yuzbasiyan-Gurkin V, et al. Initial therapy of patients with Wilson's disease with tetrathiomolybdate. Arch Neurol 1991; 48: 4247.

    • Search Google Scholar
    • Export Citation
  • 15. Brewer GJ, Terry CA, Aisen AM, et al. Worsening of neurologic syndrome in patients with Wilsons-disease with initial penicillamine therapy. Arch Neurol 1987; 44: 490493.

    • Search Google Scholar
    • Export Citation
  • 16. Klein D, Arora U, Lichtmannegger J, et al. Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease. J Hepatol 2004; 40: 409416.

    • Search Google Scholar
    • Export Citation
  • 17. Kent MS, Madewell BR, Dank G, et al. An anticopper antiangiogenic approach for advanced cancer in spontaneously occurring tumors using tetrathiomolybdate: a pilot study in a canine animal model. J Trace Elem Exp Med 2004; 17: 920.

    • Search Google Scholar
    • Export Citation
  • 18. Suzuki KT, Ogra Y, Ohmichi M. Molybdenum and copper kinetics after tetrathiomolybdate injection in LEC rats—specific role of serum-albumin. J Trace Elem Med Biol 1995; 9: 170175.

    • Search Google Scholar
    • Export Citation
  • 19. Botha CJ, Swan GE, Minnaar PP. Pharmacokinetics of ammonium tetrathiomolybdate following intravenous administration in sheep. J S Afr Vet Assoc 1995; 66: 610.

    • Search Google Scholar
    • Export Citation
  • 20. Komatsu Y, Sadakata I, Ogra Y, et al. Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats. Chem Biol Interact 2000; 124: 217231.

    • Search Google Scholar
    • Export Citation
  • 21. Humphries WR, Morrice PC, Bremner I. A convenient method for the treatment of chronic copper poisoning in sheep using subcutaneous ammonium tetrathiomolybdate. Vet Rec 1988; 123: 5153.

    • Search Google Scholar
    • Export Citation
  • 22. Keith K, Nicholson D, Rogers D. Accuracy and precision of low-dose insulin administration using syringes, pen injectors, and a pump. Clin Pediatr (Phila) 2004; 43: 6974.

    • Search Google Scholar
    • Export Citation
  • 23. Peacock G, Parnapy S, Raynor S, et al. Accuracy and precision of manufacturer-supplied liquid medication administration devices before and after patient education. Am Pharm Assoc (2003) 2010; 50: 8486.

    • Search Google Scholar
    • Export Citation
  • 24. Wahlen R, Evans L, Turner J, et al. The use of collision/reaction cell ICP-MS for the determination of elements in blood and serum samples. Spectroscopy 2005; 20: 8489.

    • Search Google Scholar
    • Export Citation
  • 25. Zhang Y, Huo M, Zhou J, et al. PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed 2010; 99: 306314.

    • Search Google Scholar
    • Export Citation
  • 26. Laurie SH. Thiomolybdates—simple but very versatile reagents. Eur J Inorg Chem 2000; 12: 24432450.

  • 27. Brewer GJ. The use of copper-lowering therapy with tetrathiomolybdate in medicine. Expert Opin Investig Drugs 2009; 18: 8997.

  • 28. Ogra Y, Ohmichi M, Suzuki KT. Systemic dispositions of molybdenum and copper after tetrathiomolybdate injection in LEC rats. J Trace Elem Med Biol 1995; 9: 165169.

    • Search Google Scholar
    • Export Citation
  • 29. Lai YR, Sugawara N. Outputs of hepatic copper and cadmium stimulated by tetrathiomolybdate (TTM) injection in Long-Evans cinnamon (LEC) rats pretreated with cadmium, and in Fischer rats pretreated with copper and cadmium. Toxicology 1997; 120: 4754.

    • Search Google Scholar
    • Export Citation
  • 30. Ogra Y, Suzuki KT. Targeting of tetrathiomolybdate on the copper accumulating in the liver of LEC rats. J Inorg Biochem 1998; 70: 4955.

    • Search Google Scholar
    • Export Citation
  • 31. Gooneratne SR, Christensen DA. Effect of chelating agents on the excretion of copper, zinc, and iron in the bile and urine of sheep. Vet J 1997; 153: 171178.

    • Search Google Scholar
    • Export Citation
  • 32. Dastych M, Prochazkova D, Pokorny A, et al. Copper and zinc in the serum, urine, and hair of patients with Wilson's disease treated with penicillamine and zinc. Biol Trace Elem Res 2010; 133: 265269.

    • Search Google Scholar
    • Export Citation
  • 33. JX, Combs GF Jr. Penicillamine—pharmacokinetics and differential-effects on zinc and copper status in chicks. J Nutr 1992; 122: 355362.

    • Search Google Scholar
    • Export Citation
  • 34. Chen DB, Feng L, Lin XP, et al. Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice. PLoS ONE 2012; 7:e37709.

    • Search Google Scholar
    • Export Citation
  • 35. Plumb DC. In: Plumb's veterinary drug handbook. 7th ed. Ames, Iowa: Wiley-Blackwell, 2011; 624626.

  • 36. Sugawara N, Li D, Sugawara C. Removal of copper from the liver of Long-Evans Cinnamon (LEC) rats by tetrathiomolybdate (TTM) injection: the main excretion route is via blood, not bile. Res Commun Mol Pathol Pharmacol 1994; 85: 217226.

    • Search Google Scholar
    • Export Citation

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Pharmacologic evaluation of ammonium tetrathiomolybdate after intravenous and oral administration to healthy dogs

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  • 1 Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
  • | 2 Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
  • | 3 Diagnostic Center for Population and Animal Health, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
  • | 4 Diagnostic Center for Population and Animal Health, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
  • | 5 Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
  • | 6 Diagnostic Center for Population and Animal Health, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.
  • | 7 Department of Pharmacology, Michigan State University In Vivo Facility, East Lansing, MI 48824.
  • | 8 Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

Abstract

OBJECTIVE To evaluate pharmacokinetics of ammonium tetrathiomolybdate (TTM) after IV and oral administration to dogs and effects of TTM administration on trace mineral concentrations.

ANIMALS 8 adult Beagles and Beagle crossbreds (4 sexually intact males and 4 sexually intact females).

PROCEDURES Dogs received TTM (1 mg/kg) IV and orally in a randomized crossover study. Serum molybdenum and copper concentrations were measured via inductively coupled plasma mass spectrometry in samples obtained 0 to 72 hours after administration. Pharmacokinetics was determined via noncompartmental analysis.

RESULTS For IV administration, mean ± SD terminal elimination rate constant, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours−1, 4.9 ± 0.6 μg/mL, 30.7 ± 5.4 μg/mL•h, and 27.7 ± 6.8 hours, respectively. For oral administration, mean ± SD terminal elimination rate constant, time to maximum concentration, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours−1, 3.0 ± 3.5 hours, 0.2 ± 0.4 μg/mL, 6.5 ± 8.0 μg/mL•h, and 26.8 ± 8.0 hours, respectively. Oral bioavailability was 21 ± 22%. Serum copper concentrations increased significantly after IV and oral administration. Emesis occurred after IV (2 dogs) and oral administration (3 dogs).

CONCLUSIONS AND CLINICAL RELEVANCE Pharmacokinetics for TTM after a single IV and oral administration was determined for clinically normal dogs. Absorption of TTM after oral administration was variable. Increased serum copper concentrations suggested that TTM mobilized tissue copper. Further studies will be needed to evaluate the potential therapeutic use of TTM in copper-associated chronic hepatitis of dogs.

Contributor Notes

Address correspondence to Dr. Langlois (langlo21@cvm.msu.edu).