A comparative study of the pharmacokinetics of intravenous and oral trimethoprim/sulfadiazine formulations in the horse |
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| Authors: | E. VAN DUIJKEREN ,A. G. VULTO,M. M. SLOET VAN OLDRUITENBORGH-OOSTERBAAN,D. J. MEVIUS&Dagger ,B. G. F. KESSELS,H. J. BREUKINK,A. S. J. P. A. M. VAN MIERTS |
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| Affiliation: | *Department of Large Animal Medicine and Nutrition.;†The Veterinary Pharmacy, Faculty of Veterinary Medicine, Utrecht University;‡Animal Health Services for West- and Central Netherlands, Ronsseweg 553, 2800 AB Gouda.;§Department of Veterinary Basic Sciences, Division of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Utrecht University, P o Box 80.152, 3508 TD Utrecht, the Netherlands |
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| Abstract: | The biopharmaceutical properties of four fuced trimethoprim/sulfonamide combinations were investigated in the horse. Eight fasted horses were dosed at 1 week intervals in a sequentially designed study with one intravenous (i.v.) and three oral trimethoprim/sulfadiazine (TMP/SDZ) formulations (1, 2 and 3) administered at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulfadiazine (SDZ). Plasma concentrations of each compound were monitored for 48 h. Pharmacokinetic parameters (volume of distribution, bioavailability and total body clearance) for TMP and SDZ were calculated and compared. After oral administration plasma concentrations of TMP and SDZ increased rapidly. With all three paste formulations, TMP peak plasma concentrations were attained within 2 h. SDZ mean peak plasma concentrations were reached at 2.59 ± 0.48 h for a commercial paste (l), and at 1.84 ± 0.66 h and 1.95 ± 0.61 h for the two self-made formulations (2 and 3). Mean peak plasma TMP concentrations (± SD) were 1.72 ± 0.36 μg/ml, 1.42 ± 0.37 μg/ml and 1.31 ± 0.36 μ g/d, and mean peak plasma SDZ concentrations 12.11 ± 4.5 5 μg/ml, 12.72 ± 3.47 μg/ml and 15.45 ± 4.74 μg/ml for preparations 1, 2 and 3. The bioavailability of TMP was 67.0 ± 20.3%, 57.7 ±21.6% and 60.9 f 18.9% and of SDZ 57.6 ± 14.8%, 59.3 ± 19.5% and 65.9 ± 5.8% for SDZ for 1, 2 and 3, respectively. Following i.v. administration TMP/SDZ plasma concentration ratios approached the optimal 1:20 ratio (It 10%) for about 5 h, but following the oral administrations this ratio was only achieved for a very short time-span. No adverse effects were seen following i.v. and oral administration. In considering the pharmacokinetic data in combination with in vitro antibacterial sensitivity data, it is concluded that treatment at a dose of 5 mg/kg TMP and 25 mg/kg SDZ with a dosing interval of 12 h can be regarded as therapeutically effective for susceptible bacteria (MIC90 0.25/4.75) for all three oral formulations. It is concluded that neither the formulation nor the addition of different excipients result in significantly different bioavailabilities. |
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