Half-lives of sulphadoxine and trimethoprim after a single intravenous infusion in cows

DAVITIYANANDA, DANIS and FOLKE RASMUSSEN: Half-lives of sulphadoxine and trimethoprim after a single intravenous infusion in cows. Acta vet. scand. 1974, 15, 356–365. — The half-life of sulphadoxine in plasma (11 hrs.) is much longer than that of trimethoprim (50–103 min.) and in accordance to this traces of sulphadoxine are demonstrated in the milk 3 days after the infusion, while trimethoprim could not be detected in milk 2 days after the infusion. The apparent volume of distribution is 0.37 for sulphadoxine and 1.14 for trimethoprim, i.e. 37 % and 114 % of the body weight, respectively.sulphadoxine; trimethoprim; half-life; cow.     

Field trials with trimethoprim and sulphadoxine

Extract

Sir, — Trimethoprim (2,4-diamino-5-(3,4,5,trimethoxy-benzyl) pyrimidine) is an inhibitor of the enzyme dihydrofolate reductase and blocks its action in bacterial cell metabolism. Sulphonamides act similarly on a different enzyme and, when the two are used in combination, clinical results are much enhanced and a synergistic effect has been shown in vitro.     

The renal clearance of inulin, creatinine, trimethoprim and sulphadoxine in horses

The clearance of inulin and creatinine were almost identical in horses, indicating that creatinine clearance can be used for estimation of the glomerular filtration rate in horses. Trimethoprim (TMP) is excreted in urine by glomerular filtration, active tubular secretion and back-diffusion. The clearance of TMP is highly influenced by urine pH, but also by the plasma concentration of the drug and by the degree of diuresis. The results indicate self-depression of the active tubular secretion of TMP at plasma concentrations above 1–2 μg/ml. The renal excretion of sulphadoxine in horses involves glomerular filtration and a pronounced back-diffusion. The clearance of sulphadoxine is dependent on urine pH and increases with increasing pH. The clearance of N⁴-acetyl sulphadoxine was higher than the clearance of the parent compound. The renal excretion of N⁴-acetyl sulphadoxine was shown to involve glomerular filtration, active tubular secretion and back-diffusion.     

Pharmacokinetics of sulphadoxine and trimethoprim in horses. Half-life and volume of distribution of sulphadoxine and trimethoprim and cumulative excretion of [14C]-trimethoprim

A proprietary combination product containing sulphadoxine and trimethoprim was administered to horses by intravenous injection. Protein-binding of sulphadoxine was dependent on the concentration in plasma and decreased from 72% at 50 μg/ml to 14% at 450 μg/ml. Sulphadoxine is eliminated from plasma in accordance with a three compartment open model. The elimination half-life was on average 14 h while the volume of distribution was found to be 0.39 1/kg. Trimethoprim was eliminated from plasma in accordance with a two compartment open model. The elimination half-life was on an average 3 h. Experiments in which trimethoprim was administered alone showed that the elimination half-life was not dependent on the simultaneous administration of sulphadoxine. About 50% of trimethoprim was bound to plasma proteins, but in contrast to sulphadoxine there was no dependence between plasma concentration and protein binding. The protein binding of trimethoprim was independent of the presence of sulphadoxine and vice versa. Experiments with ¹⁴C-labelled trimethoprim showed that it was excreted in almost equal amounts in urine and faeces. 97% of the administered dose was recovered in urine and faeces during the course of the first 4 days after administration.     

Mammary and renal excretion of chlorpromazine in goats

In experiments on goats it was found that the binding of chlorpromazine (Cpz) to the proteins in plasma and milk ranged between 91–99 and 91–97 %, respectively, and was independent of the drug concentration in the samples. The in vitro binding of chlorpromazine in whole milk (96%) was significantly higher (P<0.01) than the protein binding in skim milk (91%) because the drug was concentrated in the butterfat. The concentration of Cpz was always higher in the milk than in the corresponding plasma samples. The renal clearance of Cpz in goats with normal urine pH was very small (0.16 ml min^-1) due to the high degree of plasma protein binding and of back diffusion. The mechanisms involved during the renal excretion of Cpz in goats included glomerular filtration, probably active tubular secretion and pH dependent back diffusion.     

Pharmacokinetics of sulphadoxine and trimethoprim in sows: Influence of lactation

A potentiated sulpha drug was administered intravenously to 12 sows on the 17th day of lactation and to 4 sows in early pregnancy to study the influence of lactation on its disposition kinetics. The dose-rate of sulphadoxine (SDX) used was 12 mg/kg b.w. while that of trimethoprim (TMP) was 2.4 mg/kg b.w. The pharmacokinetic parameters of SDX showed no significant difference between lactating and pregnant sows (V _ss, 0.24±0.04 L/kg; Cl _s , 0.25±0.05 ml/min per kg: MRT, 17.08±4.48 h). SDX did not accumulate in milk, the concentrations in milk being less than the concentrations in serum at the same time. Of the pharmacokinetic parameters for TMP, only the mean residence time was significantly different between the two groups (V _ss, 1.60±0.31 L/kg; Cl _s , 4.62±1.07 ml/min per kg: MRT_lactating, 5.43±1.26 h; MRT_pregnant, 7.74±1.72 h). TMP was excreted in milk to a considerable extent, the ratio of its concentration in milk to that in serum at the same time being over 2.2. These two substances show a completely different pharmacokinetic behaviour. Even though TMP is excreted more quickly in lactating sows, adjusting the dose of this potentiated sulpha drug does not seem to be appropriate.Abbreviations AUC area under the curve - AUMC area under the first-movement curve - terminal elimination rate constant - b.w. body weight - Cl _s clearance at steady state - D dose - MRT mean residence time - SD standard deviation - SDX sulphadoxine - TMP trimethoprim - V _ss apparent volume of distribution at steady state     

Determination of trimethoprim and sulphadoxine residues in porcine tissues and plasma.

Healthy gilts and market-ready hogs were administered a single intramuscular (IM) injection of Borgal, a commercial formulation of trimethoprim-sulfadoxine (TMP-SDX), once or twice daily. The objectives were to determine if a newly-developed high-performance liquid chromatographic (HPLC) method would be suitable for measuring the residual concentrations of TMP in the plasma of these live animals, and to determine if the administration of this veterinary drug would leave measurable residues in their plasma and tissues at slaughter. Plasma and tissue concentrations of SDX and TMP from these animals were determined over a period of 14 d using thin-layer chromatography/densitometry (TLCD), and the newly-developed HPLC method, respectively. The lowest detectable limit (LDL) for SDX in plasma and tissue was 20 ppb by TLCD. The HPLC method had a LDL of 5 ppb for TMP in plasma and tissue. Both methods were then used to provide baseline data on the absorption and depletion of TMP and SDX from these healthy animals. It was observed that both TMP and SDX were readily absorbed into the blood and tissues, but TMP was eliminated much faster than SDX. No TMP residues were detected in the plasma of any of the gilts at and beyond 21 h after drug administration. Also, no TMP residues were detected in the plasma of any of the market-ready hogs 24 h after drug administration at either the label dose or twice the label dose. Sulfadoxine residues at concentrations above the maximum residue limit (MRL) of 100 ppb were, however, detected in the plasma, muscle, kidney, liver, and injection sites of hogs slaughtered 1 and 3 d after a single IM administration at the label dose. Although SDX residues were still detectable in the lungs, kidney, liver and plasma of some hogs 10 d after administration of the label dose and twice the label dose, these were below the MRL. Postmortem examination revealed necrosis and inflammation at the injection sites, but no visible deposits of the injected drug.     

Concentrations of trimethoprim and sulphadoxine in tissues from goats and a cow.

The concentration of trimethoprim and sulphadoxine in plasma and tissue from goats and a cow have been determined after a single intravenous injection. Furthermore, the concentration of the two drugs and their metabolites in plasma and tissues have been determined after continuous intravenous infusion for 2½–3 hrs. Trimethoprim was present in all tissues but brain at higher concentrations than in plasma while the concentration of sulphadoxine in the different tissues were lower than in plasma. The highest concentration of the 2 drugs and their metabolites was found in the kidney. The distribution pattern of trimethoprim and sulphadoxine was similar in cow and goats.     

Mammary blood flow and venous drainage in cows

The mammary blood flow and the udder drainage in vivo evaluated using the antipyrine absorption method has been compared with the anatomical findings in the udder after slaughtering of the experimental cows (Table 1).Because of the orientation of the valves in the perineal veins and blood samples taken in vivo it must be assumed that the perineal veins lead blood toward the veins at the udder base.It is concluded that the drainage of the udder in standing cows will primarily be through the milk veins, eventually there will be a flow of non-mammary venous blood down the external pudic veins at the udder base, as in the case of the perineal veins.     

Pharmacokinetics of sulphadoxine and trimethoprim and tissue irritation caused by two sulphadoxine-trimethoprim containing products after subcutaneous administration in pre-ruminant calves

The pharmacokinetics of sulphadoxine-trimethoprim was studied in 6 pre-ruminant calves using two different products. Product A, which contained 200 mg sulphadoxine and 40 mg trimethoprim per mL, was administered intravenously or subcutaneously at a dosage of 25 mg sulphadoxine and 5 mg trimethoprim.kg-1 bodyweight. Product B, containing 62.5 mg sulphadoxine and 12.5 mg trimethoprim per mL plus lidocaine (1 mg.mL-1), was given subcutaneously at the same dosage. After intravenous administration of product A the mean time of half-life of elimination phase (t1/2) for sulphadoxine was 12.9 h, steady-state volume of distribution (Vd(ss)) was 0.44 L.kg-1 and clearance was 0.024 L.kg-1.h-1. Respective values for trimethoprim were 1.9 h, 2.0 L.kg-1 and 0.9 L.kg-1.h-1. After subcutaneous administration, the bioavailability of sulphadoxine was 96% and 98% and the time to reach a maximum concentration was 6.3 and 8.0 h for products A and B, respectively. The Cmax for trimethoprim was higher for product A (0.49 microgram.mL-1) than for product B (0.32 microgram.mL-1) (p = 0.014). Slow absorption from the injection site appeared to delay the elimination of trimethoprim after subcutaneous administration when compared to that after intravenous administration: apparent elimination t1/2 for trimethoprim after intravenous administration of product A was 1.9 h compared to 3.9 h and 3.6 h after subcutaneous administration of products A and B, respectively. The difference between intravenous and subcutaneous administrations was statistically significant (p < 0.05). Also the mean residence time was significantly shorter (p < 0.05) after intravenous administration (2.4 h) than that after subcutaneous administration of product A (6.9 h) and B (7.1 h). The bioavailability of trimethoprim was lower than that of sulphadoxine: 76% and 74% for products A and B, respectively. All 6 calves showed pain after subcutaneous administration of product A and the injection sites were warm and showed soft oedematous reactions 5-8 cm in diameter. Three of the calves also showed some pain after subcutaneous administration of product B; the local reactions were less severe. A marked increase was seen in creatine kinase activity after subcutaneous administration of both products. Product A caused a more pronounced increase but the difference was not statistically significant. We suggest 30 mg.kg-1 at 24-h intervals or alternatively 15 mg.kg-1 at 12-h intervals as the minimum dosage of sulphadoxine-trimethoprim combination for pre-ruminant calves. Extravascular routes of administration should be avoided due to marked tissue irritation at the injection site.     

Indication of intracellular magnesium deficiency in lactating dairy cows revealed by magnesium loading and renal fractional excretion

Nine non‐pregnant, lactating dairy cows were used to study plasma and urinary magnesium concentrations ([Mg]_pl; [Mg]_u), and the urinary fractional excretion of magnesium (FE_Mg) before, during and after an 120 min intravenous magnesium (Mg) administration (2.5 mg/kg body weight). Animals received a total mixed ration, and Mg content of the diet was within recommended range. Basal mean [Mg]_pl, [Mg]_u and FE_Mg were 0.89 ± 0.09 mm , 5.92 ± 2.99 mm and 8.3 ± 9.7% respectively. For all parameters, a substantial inter‐individual variation was observed. Three cows showed suboptimal [Mg]_pl and/or [Mg]_u as well as low FE_Mg values of approximately 2% indicating an insufficient Mg supply to these animals (depressed feed intake, reduced absorption of Mg). The applied Mg challenge induced no significant change of mean [Mg]_pl in the cows because part of the excess Mg was excreted in the urine. But in five out of nine cows, a decrease of the FE_Mg, during and after an intravenous Mg load was observed showing that part of the infused Mg is used to replenish intracellular Mg pools. Thus, the existence of an intracellular Mg deficiency in these cows was unmasked by performing the Mg loading test only. Because a reduced free intracellular [Mg] impairs cell and tissue functions, the results highlight the importance of an accurate definition of the intracellular Mg status. The Mg loading test is a suitable procedure, however, for practical purposes less expensive and time consuming methods must be developed.     

Urinary pseudouridine excretion in lactating dairy cows

Introduction   A number of systems based on metabolizable protein, such as that adopted in the UK (A gricultural and F ood R esearch C ouncil 1992) have been developed to improve the accuracy of protein rationing for ruminants. Quantification of microbial protein synthesis in the rumen is a fundamental requirement of all such systems. In the UK system, microbial protein supply is predicted from an estimate of fermentable metabolizable energy intake, using a correction for the effects of level of feeding on the energetic efficiency of microbial protein synthesis. Use of such an approach is however subject to considerable error due to large variations in the energetic efficiency of microbial protein synthesis (A gricultural R esearch C ouncil 1984). Consequently there is an urgent requirement for an on-farm diagnostic marker of microbial protein supply as a basis for adjusting diets to maximize efficiency of dietary nitrogen utilization by dairy cows (D ewhurst et al. 1996). Urinary purine derivative excretion has been proposed as a noninvasive index of microbial protein supply in ruminant animals (T opps and E lliot 1965). Use of this microbial marker is based on the assumption that purines entering the duodenum are essentially microbial in origin (M c A llan 1982), and that following metabolism, their derivatives are quantitatively recovered in the urine (C hen et al. 1990; V erbic et al. 1990). Purine metabolites excreted in ruminant urine are primarily derived from the metabolism of absorbed purines, but as a consequence of tissue adenosine triphosphate and nucleic acid turnover, a proportion of purine bases are not salvaged and re-utilized, but enter catabolic pathways, constituting an endogenous loss.     

Persistent excretion of rotavirus by pregnant cows

In a study of the epizootiology and prevalence of enteropathogens which may be involved in neonatal calf diarrhoea, 10 in-calf cows from a herd with a history of rotavirus-induced calf diarrhoea were monitored over a period of six to seven months. All the cows excreted rotavirus intermittently without showing any clinical signs, and 21.8 per cent of faecal samples contained rotavirus. Reoviruses were isolated from 87 per cent of the samples from the cows, and from all the 10 calves born to them. However, rotavirus was detected in only one calf, and diarrhoea developed only in this calf even though the calves were housed in communal pens. Campylobacter jejuni was isolated from six of the 10 dams and from five of the 10 calves, not including the calf with diarrhoea. Other potential enteropathogens such as cryptosporidium, salmonella, Clostridium difficile, coronavirus and other viruses were not found, but two cows and two calves shed enterotoxigenic Escherichia coli.