Tetracycline antimicrobials have a long history of use in veterinary medicine as broad-spectrum agents active against many organisms of importance to equine medicine.1 Doxycycline is a structural isomer of tetracycline that is available in formulations for oral and parenteral administration. The oral formulation, although not approved for veterinary species, is generic and inexpensive. Intravenous administration of doxycycline to horses has caused collapse and sudden death, apparently secondary to cardiovascular effects.2 Oral administration of other tetracyclines has been associated with gastrointestinal problems such as changes in the bacterial flora and diarrhea.3–6 However, these problems, to date, have not been reported with oral administration of doxycycline in horses. In other species, doxycycline is bound to ingesta in the gastrointestinal tract, which may decrease its effect on the resident microflora.1 The oral formulation has been well tolerated and has been recommended for use at a dosage of 10 mg/kg, every 12 hours.7
One of the most common uses of doxycycline in horses is treatment for ehrlichial infections, such as equine granulocytic ehrlichiosis caused by Anaplasma phagocytophilium (formerly Ehrlichia equi) and Potomac horse fever caused by Neorickettsia risticii (formerly Ehrlichia risticii).8,9 Because these organisms have a predilection for intracellular infection of WBCs (PMNLs for A phagocytophilium and monocytic cells for N risticii), the intracellular concentrations of the drug may be more predictive of efficacy than plasma concentrations.10 Another important use of doxycycline in horses is for treatment for leptospirosis, which has been implicated in abortion outbreaks and recurrent uveitis.11,12 Results of a previous study7 indicate that doxycycline attains adequate concentrations in endometrial tissue. However, in another study,13 the drug was detectable in the vitreous humor but not in the aqueous humor. A study14 in humans revealed that ocular penetration is possible with higher doses and more frequent administration.
Orally administered doxycycline in horses does not result in plasma concentrations necessary for inhibition of some important pathogens.7 Research15,16 reveals that doxycycline is highly protein bound in plasma, which may limit its distribution. Low doses may limit the effective concentrations at the target site. Specific studies are necessary to determine the extent of protein binding in horses, the extracellular distribution, and intraocular and intracellular penetration. We hypothesized that intraocular penetration and intracellular penetration into leukocytes are possible in horses, but may require adjustment of the dosage regimens that are presently recommended.
The purpose of the study reported here was to determine the pharmacokinetics of doxycycline after single and multiple administrations at a dosage of 20 mg/kg, PO, every 12 hours, in horses. Plasma protein binding and ISF, intraocular, and intracellular doxycycline concentrations were also determined. Previous reports of sudden death from IV administration of doxycycline in horses2 precluded an accompanying IV study to determine variables such as systemic clearance, volumes of distribution, and oral systemic availability; therefore, allometric principles were applied to the data to estimate these variables.
High-pressure liquid chromatography
Peak plasma concentration
Time to peak plasma concentration
Area under the plasma concentration-time curve
Limit of quantification
Slope of the terminal phase
AUC from 0 to 12 hours
AUC extrapolated to infinity
Minimum inhibitory concentration-90%
Doxycycline hyclate tablets, 500 mg, West-ward Pharmaceutical Corp, Eatontown, NJ.
Canine ultrafiltration probe (RUF-3-12), BAS Bioanalytical Systems, West Lafayette, Ind.
Sedazine, Fort Dodge Animal Health, Fort Dodge, Iowa.
Lidocaine hydrochloride injectable-2%, Phoenix Scientific Inc, St Joseph, Mo.
Dormosedan, Pfizer Animal Health, Exton, Pa.
Proparacaine hydrochloride ophthalmic solution, Falcon Pharmaceuticals Ltd, Fort Worth, Tex.
Centrifree micropartition system, Amicon, Beverly, Mass.
Waters Pump, Millipore Corp, Milford, Mass.
Agilent Series 1100, Agilent Technologies, Wilmington, Del.
Agilent series 1050 variable wavelength detector, Agilent Technologies, Wilmington, Del.
Agilent Series 1100 Chemstation software, Agilent Technologies, Wilmington, Del.
Zorbax RX-C8 4.6 × 150-mm reverse phase column, Agilent Technologies, Wilmington, Del.
WinNonlin, version 4.0, Pharsight Corp, Mountain View, Calif.
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