A study of the pharmacokinetics and tissue residues of an oral trimethoprim/sulphadiazine formulation in healthy pigs

Abstract

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.

Pharmacokinetics and bioavailability of sulfadiazine and trimethoprim (trimazin 30%) after oral administration in non‐fasted young pigs

“…As shown by Nielsen and Gyrd‐Hansen (1994) and Garwacki et al . (1996), the absorption phase in fed pigs is somewhat prolonged and shows a large individual variation.…”

“…Trimethoprim, which has a high volume of distribution, passes rapidly from the plasma into tissues. Therefore, the TMP/SDA ratios in various tissues differ from those in the plasma (Garwacki et al ., 1996). To achieve the optimal ratio of 1:20 in plasma, a pharmaceutical dosage form which contains TMP and SDA in a 1:5 ratio was chosen.…”

“…Also values for the clearance of SDA and TMP were found in pigs: 0.14 and 0.34–0.55 L/h kg, respectively (Nielsen & Gyrd‐Hansen, 1994; Mengelers et al ., 1995). However, more variation was found in the elimination half‐life of SDA and TMP in pigs: 2.4–4.19 and 2.24–5.49 h, respectively (Nielsen & Rasmussen, 1975; Luther, 1979; Søli et al ., 1990; Nielsen & Gyrd‐Hansen, 1994; Garwacki et al ., 1996). In this experiment the elimination half‐life of SDA and TMP was practically identical ( t 1/2 β , 2.7 h).…”

Bioavailability and Pharmacokinetics of Sulphadiazine, N4-acetylsulphadiazine and Trimethoprim following Intravenous and Intramuscular Administration of a Sulphadiazine/Trimethoprim Combination in Sheep

“…Studies in other species, such as swine (Nielsen and Rasmussen, 1975a,b;Garwacki et al, 1996), dogs and cats (Craig and White, 1976;Sigel et al, 1981), horses (Brown et al, 1983;Bogan et al, 1984;Van Duijkeren et al, 1994a, Gustafsson et al, 1999, poultry (Lo« scher et al, 1990;Batzias et al, 2000;Baert et al, 2003), rabbits (Ladefoged, 1977) and ¢sh (Nouws et al, 1993), have also been performed. All investigators clearly reported higher values of volume of distribution (V) and clearance (Cl), together with a substantially shorter elimination half-life for TMP, compared to SDZ.…”

A pharmacokinetic and residual study of sulfadiazine/trimethoprim in mandarin fish (Siniperca chuatsi) with single‐ and multiple‐dose oral administrations

“…To our knowledge, there is a lack of information at present regarding the pharmacokinetic behavior of SDZ and TMP in mandarin fish. Several pharmacokinetic studies of SDZ, TMP, or both have been conducted in other species such as chickens (Baert et al ., ), cattle and calves (Shoaf et al ., ; Kaartinen et al ., ), ponies and horses (Van Duijkeren et al ., , ), dogs (Sigel et al ., ), pigs (Baert et al ., ; Garwacki et al ., ), and ostrich (Abu‐Basha et al ., ). This study evaluates the pharmacokinetic and residual parameters of SDZ and TMP and discusses their rational ratio in mandarin fish for well treatment of bacterial diseases.…”