Pharmacokinetics of Aditoprim, a New Long‐acting Dihydrofolate Reductase Inhibitor, in Heifers

Abstract

The pharmacokinetics of aditoprim, a new dihydrofolate reductase (DHFR) inhibitor, and trimethoprim (TMP) were studied in heifers following a single intravenous injection of a 10rng/kg b. w. dose. Aditoprim had a larger volume of distribution at steady state (6.5 k 0.6 Pkg) than TMP (1.1 +_ 0.1 I/kg) and this probably reflects a better tissue penetration than TMP. Both antimicrobials had the same high plasma clearance (5.0 k 1 .O Urnin). Accordingly, aditoprim exhibited a longer halflife (4-6.711) than TMP which was 1.3h, as reported by several authors. Moreover, the plasma concentrations of the new antimicrobial were higher than those of TMP, starting from 4 hours after the drug was injected. For these reasons, the duration of the in vivo bacteriostatic activity of aditoprim should be significantly longer than that of TMP.Aditoprim was also injected intravenously into heifers in combination with either sulphadimidine (SDM) or sulphamerazine (SMR) in a 5:l w/w sulphonamide/aditoprim ratio. The dose was 15 mg of the combination/kg b. w. The pharmacokinetics of the two combinations showed no significant differences. The half-lives of SDM and SMR were both 4 hours, and the pharmacokinetic parameters of aditoprim did not differ significantly from those found when the drug was injected alone. Thus, the half-life of the new DHFR inhibitor appeared to be in the same range as that of the sulphonamides commonly used in veterinary medicine, while its antimicrobial activity was considerably higher. The use of aditoprim as a single drug could thus be envisaged as well as in combination with a sulphonamide.

Metabolism and Disposition of Aditoprim in Swine, Broilers, Carp and Rats

“…In contrast to the excretion of TMP in rats, more than 95% of the oral dose was recovered within 3 d. ADP showed a relatively slow elimination trend (approximately 84% of the oral dose during 0–3 d) in comparison with the rat excreta, implying that ADP would have a longer elimination half-life than TMP in the organism. This finding was further supported by the pharmacokinetic characteristics of ADP in animals 5 6 8 . ADP related radioactivity in broilers was excreted more rapidly than in other species, with a high recovery of 85.8% (about 70% in other species, Fig.…”

“…It is reported that this compound is particularly active against Enterobacteriaceae , Haemophilus , Staphylococcus , Streptococcus , Vibrio , and Aeromonas 2 . Moreover, ADP provides significant pharmacokinetic advantages, including long half-lives (6.1–11.9 h) and high tissue distribution volume (4.4–12.2 L/kg) in various animal species such as sheep 3 4 5 , cattle 6 7 8 9 , pig 10 , horse 11 , turkey 12 , dog 13 , and monkey 14 . These earlier studies have shown that ADP had a good efficacy when administered alone or combined with sulfonamides in a one-day dose for the treatment of respiratory and gastro-intestinal infections.…”

Pharmacokinetics of aditoprim, a dihydrofolate reductase inhibitor, in sheep

“…The These drugs are widely used in veterinary medicine (Vree & Hekster, 1985). The apparent volume of distribution, about 5 Vkg, indicated that aditoprim is widely distributed in the body, as has already been observed in pigs (26 Vkg;Ludwig et al, 1985) and cattle (25 I/kg ;Jordan et al, 1986). This value was more than five-and ten-times higher than for TMP and sulphonamides, respectively, and reflects the good tissue penetration of the new antimicrobial.…”

The biotransformation of sulfadimethoxine, sulfadimidine, sulfamethoxazole, trimethoprim and aditoprim by primary cultures of pig hepatocytes

“…The elimination half-life of ADP in pigs is & 8 h, whereas the half-life of TMP is 2.5±3 h (Nielsen & Rasmussen, 1975;Ludwig et al, 1985;Jordan et al, 1987). This may be due to the fact that ADP is not metabolized to polar compounds with high renal clearance rates, like the glucuronidated O-demethyl derivatives of TMP (Van`t Klooster et al, 1994a).…”