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Twenty-six healthy female pigs weighing 19.5-33 kg were used in three separate experiments. The animals were fed individually twice a day. Trimethoprim/sulphadiazine (TMP/SDZ) formulation was added to feed in the amount of 6 mg/kg bw (TMP) and 30 mg/kg bw (SDZ). TMP and SDZ concentrations in blood plasma, muscles, liver and kidneys were measured. Pharmacokinetic parameters show that the absorption of TMP from the alimentary tract in pigs is faster than the absorption of SDZ, and the elimination of TMP is slower than that of SDZ. The absorption half-lives were 0.96 (TMP) and 2.24 h (SDZ), whereas elimination half-lives were 5.49 (TMP) and 4.19 h (SDZ). The observed TMP:SDZ ratios in blood plasma after multiple dose administration ranged from 1:11.4 to 1:23.2. One day after administration of the last dose of TMP/SDZ the plasma concentration ratio was 1:15.5, but in muscles, liver and kidneys it was much lower: 1:0.79, 1:0.14 and 1:1.53 respectively. The absolute TMP and SDZ tissue concentrations 1 day after the last multiple dose administration were very low (maximum TMP: 0.29 micrograms/g in liver; maximum SDZ: 0.23 micrograms/g in kidneys). Neither drug was detected in any tissue 8 days after the last administration of TMP/SDZ. Based on our results, it was concluded that there is no support for the TMP:SDZ pharmaceutical ratio 1:5 in oral formulations of these compounds for pigs. The administration oral TMP/SDZ formulations once a day may result in the absolute tissue concentrations of these drugs being too low for antibacterial activity. The withdrawal period for such an oral TMP/SDZ formulation for pigs (according to accepted guidelines in Europe for MRL of TMP < 0.05 mg/kg of tissue) should not be less than 5 days.

It was found in previous experiments that an increased concentration of ammonia in the blood of sheep caused changes of the level of certain blood metabolites (glucose, lactate, pyruvate and free fatty acids) similar to those induced by adrenaline [Barej, Garwacki, Kulasek and Wiechetek, 1974; Wiechetek, Garwacki and Barej, 1975]. It was suggested from these findings that the ammonium ions might stimulate release of catecholamines which in turn could produce the metabolic changes observed. This suggestion has also been made by Feldman and Lebovitz [1971] and Prior, Clifford, Gibson and Visek [1971].The effect of adrenaline can be eliminated or markedly reduced by application of substances blocking adrenergic receptors. Wiechetek, Garwacki and Barej [1975] studied the metabolic effect of ammonium chloride in sheep after the infusion of phentolamine, an oc-receptor blocking agent. Blockade of areceptors prevented the hyperglycaemnic response to both ammonia and adrenaline infusions. The blockade did not greatly influence the effect of either substance on lipid mobilization.It was suggested by Basset [1970] and Himms-Hagen [1972] that the lipolytic effect of adrenaline in sheep is mainly exerted through the /B-adrenergic receptor activity. It was the purpose of the present study to determine the effects of ammonium ions and adrenaline on the level of some blood metabolites of sheep after administration of propranolol as a /3-receptor blocking agent. MethodsThe experiments were carried out on 24 individually fed Merino-Precose ewes weighing 50-55 kg receiving a concentrate ration which consisted of ground 23

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[Brosnan and Williamson, 1974]. Barej, Garwacki, Kulasek and Wiechetek [1974] showed an increase in blood glucose and free fatty acids following intravenous ammonium chloride.The mechanism of action of the ammonium ion on intermediary metabolism is not well understood: ammonia passes fairly readily across cell membranes, hence a direct effect on cellular enzymes might be expected, and numerous enzymes are sensitive to ammonia, the effect depending largely on ammonia concentration [Katunuma and Okada, 1963; Katunuma, Okada and Nishii, 1966; Kulasek, Siwecka, Owczarczyk, Rynica and Barej, 1974]. Some authors suggest that the metabolic action of ammonia is mediated by catecholamines [Feldman and Lebovitz, 1971; Prior, Clifford, Gibson and Visek, 1971]. This suggestion prompted the present investigation in which the effects of ammonium chloride and adrenaline were compared after phentolamine blockade of the a-adrenergic receptors in sheep.