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(1) In order to make trimethoprim (TMP) available to broilers throughout the day, a sustained release formulation (SRF) of the drug in the form of granules was added to the water tank that supplies drinking water. (2) Broilers were initially dosed with sulphachloropiridazine-TMP (SCP-TMP 5:1) and then further medicated throughout the day, achieving in the end a dose of 30 mg/kg each of SCP and TMP (group A). Group B received a preparation with the same dose of SCP and TMP (1:1) as group A, but administered as a single dose without the SRF of TMP. Group C received the customary SCP-TMP 5:1 preparation (30 and 6 mg/kg, respectively). Water tanks were completely consumed in 3 to 4 h. (3) Broilers were bled at different times and concentration of antibacterial activity in serum determined by correlating the composite antibacterial activity of SCP and TMP with actual concentrations of these drugs by means of a microbiological agar diffusion assay. (4) Time vs serum concentrations of activity were higher in group B; the increments in the maximum serum concentration for group B over groups A and C being 39 and 67%, respectively. (5) However, the sustained concentration of activity over time, measured as the area under the cu)rve, was highest in group A. Group B had higher values for area under the curve than group C. (6) An additional dose of TMP to achieve 30 mg/kg of both SCP and TMP improves the serum concentration of this combination over the customary 5:1 proportion. The best values for sustaining antibacterial activity were obtained using a 1:1 ratio as in group A. The use of a SRF as in group A may translate into better clinical results.

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Binding of antibiotics to food has received little attention in equine medicine, although such binding could potentially reduce the bioavailability and clinical efficacy. In the present study, binding of trimethoprim (TMP) and sulphachlorpyridazine (SCP) to hay, grass silage and concentrate was investigated in vitro in buffer at pH 6.8 at different concentrations. The binding of TMP and SCP to caecal contents was also studied. In addition, the degradation of TMP and SCP by the caecal microflora was investigated by incubating sterilized and non-sterilized caecal contents for 3 h at 37 degrees C under anaerobic conditions and comparing the TMP and SCP contents. Further, a TMP/SCP powder formulation was adminstered orally with concentrate at a dose rate of 5 mg/kg TMP and 25 mg/kg SCP to three ponies with a caecum fistula; the animals were deprived of food for 8 h before administration. Blood samples, caecal contents samples and faecal samples were collected and analysed for TMP and SCP concentrations by means of high performance liquid chromatography (HPLC). Three non-fistulated ponies, acting as control animals, were fed the same dose of TMP/SCP with concentrate after 8 h of food deprivation and blood samples were taken. The percentage of in vitro binding of TMP as well as SCP to hay, grass silage and concentrate at concentrations of 4 micrograms/mL to 10 micrograms/mL was high (60-90%). TMP and SCP were also extensively bound to caecal contents (50-70%). At spiking concentrations above 10 micrograms/mL the percentage of binding decreased. There was no evidence of biodegradation of TMP or SCP in caecal contents. In vivo, both drugs could be detected in the caecal contents and in the faeces of three fistulated ponies. However, the fistulated ponies differed from the control ponies in that their TMP and SCP plasma concentrations were higher, and two fistulated ponies did not show double peaks in their plasma concentration-time curves. Therefore, the fistulated ponies did not provide an optimal model for in vivo binding studies. Despite this limitation, it can be concluded that binding of TMP and SCP to food is a major cause of the limited bioavailability of these drugs in the horse. It is hypothesized that the binding is reversible, and that a second absorption phase occurs in the large intestine, but part of the administered dose remains bound as both drugs were found in the faeces.

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In the present study, the pharmacokinetic parameters of a trimethoprim/sulphachlorpyridazine preparation following intravenous administration, administration by nasogastric tube and administration with concentrate were determined in the horse. Eight adult horses were dosed at 1 week intervals in a sequentially designed study at a dose of 5 mg/kg trimethoprim (TMP) and 25 mg/kg sulphachlorpyridazine (SCP) on all occasions. Plasma concentrations of both drugs were measured serially for 48 h. Pharmacokinetic parameters of clinical importance (distribution and elimination half-lives, clearance, bioavailability, volume of distribution) were determined both for TMP and SCP. Following intravenous administration, the volume of distribution at steady-state (Vd(ss)) was significantly larger for TMP (1.51 +/- 0.25 L/kg than for SCP (0.26 +/- 0.05 L/kg. The clearance was 7.73 +/- 2.26 mL/min.kg for TMP and 2.64 +/- 0.48 mL/min.kg for SCP. For both TMP and SCP, mean peak plasma concentrations (Cmax) and the bioavailabilities (F) were reduced significantly when the drugs were mixed with concentrate (ct) as compared with those after nasogastric administration (ngt) (Fct = 44.3 +/- 10.7% vs. Fngt = 68.3 +/- 12.5% for TMP; Fct = 46.3 +/- 8.9% vs. Fngt = 67.3 +/- 13.7% for SCP). Following the administration of TMP and SCP mixed with concentrate, the plasma concentration-time curves showed a biphasic absorption pattern in all horses. The first peak occurred 1-2 h and the second peak 8-10 h after administration of the combination preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

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The pharmacokinetics of sulfachloropyridacine were studied in a series of 30 adult patients (healthy volunteers, patients with moderate hepatic impairment and patients with renal impairment). In all cases a 500 mg dose of sodium sulfachloropyridacine was administered orally. The drug follows a single compartment pharmacokinetic model. In healthy patients the following pharmacokinetic parameters were established: Ka = 5.130 h-1, Ke = 0.205 h-1, tmax = 40 min, Vd = 7.94 liters, and in patients diagnosed with cirrhosis a decrease is appreciable in the absorption constant and in the area below the blood-time levels curve. A linear relationship is established between the elimination constant and creatinine clearance. A dosage regimen, applicable to patients with renal impairment, is established as a function of the pharmacokinetic parameters. The degree of plasma protein binding of sulfachloropyridacine diminishes significantly in patients with renal impairment.

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The half-lives, apparent volume of distribution and protein-binding of 11 sulphonamides were determined in 89 experiments on 49 cows. The estimations of half-lives indicated the presence of a distribution phase (alpha-phase) for all the sulphonamides investigated with the exception of sulphachloropyridazine. The elimination half-life (beta-phase) of the sulphonamides in plasma varied from 70 to 1000 min and was positively correlated with the solubility of the compounds in organic solvents. This was explained by the greater reabsorption of the more fat-soluble compounds in the kidneys. All the sulphonamides except sulphadimidine had a shorter half-life in cows than previously reported from human investigations. The apparent volume of distribution was about one for sulphanilamide and lower for all the other sulphonamides investigated. The protein-binding estimated in vitro agreed well with the in vivo results. It was slightly lower than in humans and the degree of protein-binding decreased with increasing sulphonamide concentration in plasma.

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