Pharmacokinetics of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits

F. Sampieri; J. Alcorn; A. L. Allen; C. R. Clark; F. A. Vannucci; N. Pusterla; S. Mapes; K. R. Ball; P. M. Dowling; J. Thompson; L. R. Bernstein; C. J. Gebhart; D. L. Hamilton

doi:10.1111/jvp.12114

Pharmacokinetics of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits

F. Sampieri, J. Alcorn, A. L. Allen, C. R. Clark, F. A. Vannucci, N. Pusterla, S. Mapes, K. R. Ball, P. M. Dowling, J. Thompson, L. R. Bernstein, C. J. Gebhart, D. L. Hamilton

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Abstract

Oral gallium maltolate (GaM) pharmacokinetics (PK) and intestinal tissue (IT) concentrations of elemental gallium ([Ga]) and iron ([Fe]) were investigated in a rabbit model of equine proliferative enteropathy (EPE). New Zealand white does (uninfected controls and EPE-infected, n = 6/group) were given a single oral GaM dose (50 mg/kg). Serial blood samples were collected from 0 to 216 h post-treatment (PT) and IT samples after euthanasia. Serology, qPCR, and immunohistochemistry confirmed, or excluded, EPE. Blood and IT [Ga] and [Fe] were determined using inductively coupled plasma–mass spectrometry. PK parameters were estimated through noncompartmental approaches. For all statistical comparisons on [Ga] and [Fe] α = 5%. The Ga log-linear terminal phase rate constant was lower in EPE rabbits vs. uninfected controls [0.0116 ± 0.004 (SD) vs. 0.0171 ± 0.0028 per hour; P = 0.03]; but half-life (59.4 ± 24.0 vs. 39.4 ± 10.8 h; P = 0.12); C_max (0.50 ± 0.21 vs. 0.59 ± 0.42 μg/mL; P = 0.45); t_max (1.75 ± 0.41 vs. 0.9 ± 0.37 h; P = 0.20); and oral clearance (6.743 ± 1.887 vs. 7.208 ± 2.565 L/h; P = 0.74) were not. IT's [Ga] and [Fe] were higher (P < 0.0001) in controls. In conclusion, although infection reduces IT [Ga] and [Fe], a 48 h GaM dosing interval is appropriate for multidose studies in EPE rabbits.

Original language	English (US)
Pages (from-to)	486-499
Number of pages	14
Journal	Journal of Veterinary Pharmacology and Therapeutics
Volume	37
Issue number	5
DOIs	https://doi.org/10.1111/jvp.12114
State	Published - 2014

Bibliographical note

Funding Information:
Our sincerest thanks are extended to R.T. Orchard, DVM; K.M.N. MacLellan, DVM; K.C. Smith, DO; and Ms. A.J. Anto-nopoulos, BSc, for their help during sample collection; to the ACU personnel at the Western College of Veterinary Medicine, University of Saskatchewan, for their expert technical support; and to Ms. A. Gebhart for her help with editing the manuscript. This study was funded by a 2009 Equine Health Research Fund Grant at the Western College of Veterinary Medicine, University of Saskatchewan. Drs. Sampieri and Ball were fellows of the CIHR-THRUST (Canadian Institutes of Health Research – Training Grant in Health Research Using Synchrotron Techniques) Grant. Dr. Vannucci was supported by the Brazilian Government sponsoring agency ‘Conselho Nacional de Desenvolvimento Cientifico e Tecnologico’ (CNPq).

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© 2014 John Wiley & Sons Ltd

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Sampieri, F., Alcorn, J., Allen, A. L., Clark, C. R., Vannucci, F. A., Pusterla, N., Mapes, S., Ball, K. R., Dowling, P. M., Thompson, J., Bernstein, L. R., Gebhart, C. J., & Hamilton, D. L. (2014). Pharmacokinetics of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits. Journal of Veterinary Pharmacology and Therapeutics, 37(5), 486-499. https://doi.org/10.1111/jvp.12114

Sampieri, F, Alcorn, J, Allen, AL, Clark, CR, Vannucci, FA, Pusterla, N, Mapes, S, Ball, KR, Dowling, PM, Thompson, J, Bernstein, LR, Gebhart, CJ & Hamilton, DL 2014, 'Pharmacokinetics of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits', Journal of Veterinary Pharmacology and Therapeutics, vol. 37, no. 5, pp. 486-499. https://doi.org/10.1111/jvp.12114

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title = "Pharmacokinetics of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits",

abstract = "Oral gallium maltolate (GaM) pharmacokinetics (PK) and intestinal tissue (IT) concentrations of elemental gallium ([Ga]) and iron ([Fe]) were investigated in a rabbit model of equine proliferative enteropathy (EPE). New Zealand white does (uninfected controls and EPE-infected, n = 6/group) were given a single oral GaM dose (50 mg/kg). Serial blood samples were collected from 0 to 216 h post-treatment (PT) and IT samples after euthanasia. Serology, qPCR, and immunohistochemistry confirmed, or excluded, EPE. Blood and IT [Ga] and [Fe] were determined using inductively coupled plasma–mass spectrometry. PK parameters were estimated through noncompartmental approaches. For all statistical comparisons on [Ga] and [Fe] α = 5%. The Ga log-linear terminal phase rate constant was lower in EPE rabbits vs. uninfected controls [0.0116 ± 0.004 (SD) vs. 0.0171 ± 0.0028 per hour; P = 0.03]; but half-life (59.4 ± 24.0 vs. 39.4 ± 10.8 h; P = 0.12); Cmax (0.50 ± 0.21 vs. 0.59 ± 0.42 μg/mL; P = 0.45); tmax (1.75 ± 0.41 vs. 0.9 ± 0.37 h; P = 0.20); and oral clearance (6.743 ± 1.887 vs. 7.208 ± 2.565 L/h; P = 0.74) were not. IT's [Ga] and [Fe] were higher (P < 0.0001) in controls. In conclusion, although infection reduces IT [Ga] and [Fe], a 48 h GaM dosing interval is appropriate for multidose studies in EPE rabbits.",

author = "F. Sampieri and J. Alcorn and Allen, {A. L.} and Clark, {C. R.} and Vannucci, {F. A.} and N. Pusterla and S. Mapes and Ball, {K. R.} and Dowling, {P. M.} and J. Thompson and Bernstein, {L. R.} and Gebhart, {C. J.} and Hamilton, {D. L.}",

note = "Funding Information: Our sincerest thanks are extended to R.T. Orchard, DVM; K.M.N. MacLellan, DVM; K.C. Smith, DO; and Ms. A.J. Anto-nopoulos, BSc, for their help during sample collection; to the ACU personnel at the Western College of Veterinary Medicine, University of Saskatchewan, for their expert technical support; and to Ms. A. Gebhart for her help with editing the manuscript. This study was funded by a 2009 Equine Health Research Fund Grant at the Western College of Veterinary Medicine, University of Saskatchewan. Drs. Sampieri and Ball were fellows of the CIHR-THRUST (Canadian Institutes of Health Research – Training Grant in Health Research Using Synchrotron Techniques) Grant. Dr. Vannucci was supported by the Brazilian Government sponsoring agency {\textquoteleft}Conselho Nacional de Desenvolvimento Cientifico e Tecnologico{\textquoteright} (CNPq). Publisher Copyright: {\textcopyright} 2014 John Wiley & Sons Ltd",

year = "2014",

doi = "10.1111/jvp.12114",

language = "English (US)",

volume = "37",

pages = "486--499",

journal = "Journal of Veterinary Pharmacology and Therapeutics",

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T1 - Pharmacokinetics of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits

AU - Sampieri, F.

AU - Alcorn, J.

AU - Allen, A. L.

AU - Clark, C. R.

AU - Vannucci, F. A.

AU - Pusterla, N.

AU - Mapes, S.

AU - Ball, K. R.

AU - Dowling, P. M.

AU - Thompson, J.

AU - Bernstein, L. R.

AU - Gebhart, C. J.

AU - Hamilton, D. L.

N1 - Funding Information: Our sincerest thanks are extended to R.T. Orchard, DVM; K.M.N. MacLellan, DVM; K.C. Smith, DO; and Ms. A.J. Anto-nopoulos, BSc, for their help during sample collection; to the ACU personnel at the Western College of Veterinary Medicine, University of Saskatchewan, for their expert technical support; and to Ms. A. Gebhart for her help with editing the manuscript. This study was funded by a 2009 Equine Health Research Fund Grant at the Western College of Veterinary Medicine, University of Saskatchewan. Drs. Sampieri and Ball were fellows of the CIHR-THRUST (Canadian Institutes of Health Research – Training Grant in Health Research Using Synchrotron Techniques) Grant. Dr. Vannucci was supported by the Brazilian Government sponsoring agency ‘Conselho Nacional de Desenvolvimento Cientifico e Tecnologico’ (CNPq). Publisher Copyright: © 2014 John Wiley & Sons Ltd

PY - 2014

Y1 - 2014

N2 - Oral gallium maltolate (GaM) pharmacokinetics (PK) and intestinal tissue (IT) concentrations of elemental gallium ([Ga]) and iron ([Fe]) were investigated in a rabbit model of equine proliferative enteropathy (EPE). New Zealand white does (uninfected controls and EPE-infected, n = 6/group) were given a single oral GaM dose (50 mg/kg). Serial blood samples were collected from 0 to 216 h post-treatment (PT) and IT samples after euthanasia. Serology, qPCR, and immunohistochemistry confirmed, or excluded, EPE. Blood and IT [Ga] and [Fe] were determined using inductively coupled plasma–mass spectrometry. PK parameters were estimated through noncompartmental approaches. For all statistical comparisons on [Ga] and [Fe] α = 5%. The Ga log-linear terminal phase rate constant was lower in EPE rabbits vs. uninfected controls [0.0116 ± 0.004 (SD) vs. 0.0171 ± 0.0028 per hour; P = 0.03]; but half-life (59.4 ± 24.0 vs. 39.4 ± 10.8 h; P = 0.12); Cmax (0.50 ± 0.21 vs. 0.59 ± 0.42 μg/mL; P = 0.45); tmax (1.75 ± 0.41 vs. 0.9 ± 0.37 h; P = 0.20); and oral clearance (6.743 ± 1.887 vs. 7.208 ± 2.565 L/h; P = 0.74) were not. IT's [Ga] and [Fe] were higher (P < 0.0001) in controls. In conclusion, although infection reduces IT [Ga] and [Fe], a 48 h GaM dosing interval is appropriate for multidose studies in EPE rabbits.

AB - Oral gallium maltolate (GaM) pharmacokinetics (PK) and intestinal tissue (IT) concentrations of elemental gallium ([Ga]) and iron ([Fe]) were investigated in a rabbit model of equine proliferative enteropathy (EPE). New Zealand white does (uninfected controls and EPE-infected, n = 6/group) were given a single oral GaM dose (50 mg/kg). Serial blood samples were collected from 0 to 216 h post-treatment (PT) and IT samples after euthanasia. Serology, qPCR, and immunohistochemistry confirmed, or excluded, EPE. Blood and IT [Ga] and [Fe] were determined using inductively coupled plasma–mass spectrometry. PK parameters were estimated through noncompartmental approaches. For all statistical comparisons on [Ga] and [Fe] α = 5%. The Ga log-linear terminal phase rate constant was lower in EPE rabbits vs. uninfected controls [0.0116 ± 0.004 (SD) vs. 0.0171 ± 0.0028 per hour; P = 0.03]; but half-life (59.4 ± 24.0 vs. 39.4 ± 10.8 h; P = 0.12); Cmax (0.50 ± 0.21 vs. 0.59 ± 0.42 μg/mL; P = 0.45); tmax (1.75 ± 0.41 vs. 0.9 ± 0.37 h; P = 0.20); and oral clearance (6.743 ± 1.887 vs. 7.208 ± 2.565 L/h; P = 0.74) were not. IT's [Ga] and [Fe] were higher (P < 0.0001) in controls. In conclusion, although infection reduces IT [Ga] and [Fe], a 48 h GaM dosing interval is appropriate for multidose studies in EPE rabbits.

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DO - 10.1111/jvp.12114

M3 - Article

AN - SCOPUS:85006375120

SN - 0140-7783

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JO - Journal of Veterinary Pharmacology and Therapeutics

JF - Journal of Veterinary Pharmacology and Therapeutics

IS - 5

ER -

Pharmacokinetics of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits

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