Some pharmacokinetic data of aditoprim and trimethoprim in healthy and tick‐borne fever infected dwarf goats

Abstract

Aditoprim (AP) is a new dihydrofolate reductase inhibitor, which is structurally related to trimethoprim (TMP). The pharmacokinetics of AP (10 mg/kg) and TMP (20 mg/kg) were assessed in healthy dwarf goats. Therapeutic efficacy against rickettsial infections was tested in tick-borne fever (TBF) infected goats. The animals were given TMP (n = 5) or AP (n = 5) by i.v. injection, and subsequently the drugs were administered orally (same groups, similar doses). Finally, both groups were infected with TBF and the i.v. experiment was repeated. Plasma concentration-time curves for both drugs followed first-order two-compartment decay. For TMP, mean t1/2 beta +/- SEM (h) was 0.84 +/- 0.06 (i.v. control) and 0.90 +/- 0.06 (i.v. infected), respectively, whereas for AP values of 8.00 +/- 0.31 (i.v. control) and 10.28 +/- 0.67 (i.v. infected) were obtained (P less than 0.05). Mean Vd beta +/- SEM values (l/kg) were 3.84 +/- 0.27 (i.v. control) and 4.07 +/- 0.85 (i.v. infected) for TMP (NS) and 7.02 +/- 0.63 vs 9.29 +/- 0.21 (P less than 0.05) for AP. After i.v. injection, rumen fluid concentrations of AP were significantly (P less than 0.05) higher and more persistent than those of TMP. For AP, the plasma and rumen fluid concentrations at 3 h were 1.20 +/- 0.06 micrograms/ml and 0.85 +/- 0.17 microgram/ml, respectively. After oral administration of TMP, Cmax in plasma was 0.12 +/- 0.01 microgram/ml and the maximum was reached after 1.2 +/- 0.16 h; systemic bioavailability (F) was 10.3% (relative to AUC i.v.). Oral treatment with AP resulted in a Cmax value of 0.21 +/- 0.02 microgram/ml with Tmax of 22.5 +/- 1.65 h and a F value of 71%. Based on WBC, serum ALP and rectal temperature responses, it was concluded that both TMP and AP were inactive against Ehrlichia phagocytophila.

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

“…administration was substantially di¡erent from that of SDZ. TMP t1 2 l z was very short (0.59+0.19 h), in accordance with previous ¢ndings in sheep (43.6+2.27 min, Atef et al, 1978), calves (0.9+0.1 h in 42-day-old animals, Shoaf et al, 1989) and goats (40+5 min in adult animals, Nielsen and Rasmussen, 1976b; 0.84+0.06 h in healthy goats, Knoppert et al, 1988). However, it was signi¢cantly shorter than the elimination half-life observed in lactating cows (1.2 h, Kaartinen et al, 1999), horses (1.91+0.29 h, Brown et al, 19832.74+0.55 h, Van Duijkeren et al, 1994a;2.8 h, Gustafsson et al, 1999), swine (135+44 min, Rasmussen, 1975b), dogs (2.51 h, Sigel et al, 1981) and chickens (2.9 h, Batzias et al, 2000;1.16 h, Baert et al, 2003).…”

The influence of age on the pharmacokinetics of aditoprim in pigs after intravenous and oral administration

“…However, in goats, the bioavailability of aditoprim was found to be many times superior to that of trimethoprim (71 _+. 8.9% vs 10.3 _ 3.2% ;Knoppert et aL, 1988). In dogs, the bioavailability of aditoprim is 90.3 ---0.9% (Sutter et al, …”

“…The in vitro bacteriostatic activity of aditoprim is, like that of its parent trimethoprim, excellent against both Gram-positive and Gram-negative bacteria, although Bordetella bronchiseptica demonstrated natural resistance to DHFR inhibitors (Mengelers et aL, 1990). The pharmacoldnetics of aditoprim has been determined in calves and pigs (Ludwig et al, 1985;Sutter et al, 1992), heifers , cows (Lohuis et aL, 1992), sheep (H/inni et aL, 1987), goats (Knoppert et al, 1988), horses (Von FeUenberg et aL, 1990) and dogs (Sutter et al, 1991). In all the species studied, the elimination half-life of aditoprim is longer and its volume of distribution is larger than that of trimethoprim.…”

Research Note: Pharmacokinetics of Aditoprim in Turkeys After Intravenous and Oral Administration

“…The pharmacokinetics of aditoprim, a reversible dihydrofolate reductase inhibitor in the preclinical study phase, have already been documented in cattle (Ludwig et ah, 1985;Jordan et ah, 1987;Lohuis et al, 1992;Sutter et al, 1993), sheep (Hanni et al, 1987), goats (Knoppert et al, 1988), pigs (Ludwig et al, 1985;Riond et al, 1992), horses (von Fellenberg et al, 1990), and dogs (Sutter et al, 1991). In these species, aditoprim is characterized by a long plasma elimination half-life ranging from 6.7 to 12.5 h and a volume of distribution larger than 4.4 L/kg.…”