Serum activity/concentration profiles of a sustained-released formulation of sulphathiazole-trimethoprim (2.5:1) in calves.

Thirty-six two-week-old healthy Holstein-Friesian calves weighing between 52 and 58 kg were divided at random into three groups of 12; group A calves were given a single oral bolus containing 2.5 g sulphathiazole and 1 g trimethoprim in a sustained-release formulation; group B received the same doses of the drugs but the trimethoprim was not in a sustained-release formulation; group C received a bolus containing 2.5 g sulphathiazole and 0.5 g conventional trimethoprim. Blood samples were collected at intervals for two days, the serum was separated and the composite antibacterial activity profiles of the mixture were analysed by an agar-diffusion microbiological method. The mean maximum activities in the serum of the three groups were 23.4 microg/ml in group A, 9.25 microg/ml in group B and 8.01 microg/ml in group C. The mean areas under the curves of the serum activity time curves were 838 microg/ml/hour in group A, 216 microg/ml/hour in group B and 182 microg/ml/hour in group C.

Effect of Haemonchus contortus infection on the clearance of antipyrine, sulfobromophthalein, chloramphenicol, and sulfathiazole in lambs.

A study was made to determine the effect of Haemonchus contortus parasitic infection in lambs on the clearance of several IV administered drugs. Clearance of sulfobromophthalein or sulfathiazole from the plasma of lambs was unaffected by infection with H contortus. Clearance of antipyrine was enhanced by the infection, and thiabendazole treatment did not alter this effect. Clearance of chloramphenicol (CAP), administered as the succinate ester (CAPS), was not changed by the infection, but it was increased after treatment with thiabendazole. Changes in the mean body residence time and initial plasma concentration of CAPS and CAP after treatment with thiabendazole indicate that hydrolysis of CAPS to CAP was reduced. High concentrations of CAPS apparently enhanced its own elimination directly rather than via the expected sequence involving hydrolysis, glucuronidation, and excretion of CAP-glucuronide. Enhanced clearance of antipyrine following infection of lambs with H contortus can be explained in at least 2 ways. First, it is possible that the lambs did not have mature amounts of hepatic drug metabolizing enzyme activity as reported by other investigators, which may be explained by breed differences or animal husbandry practices. Second, infection of lambs by H contortus may have triggered an inductive response in hepatic cytochrome P-450-mediated activities, which might result via a generalized enhancement in hepatic protein synthesis associated with the physiologic response to replace plasma proteins and other blood components lost through gastrointestinal hemorrhage caused by the active feeding of adult worms. Other phase-II reactions such as acetylation, glucuronidation, and glutathione-S-transferase apparently were not affected.

The effect of nitrite on 14C-sulphathiazole (4-amino-N-2-thiazolyl[U-14C]benzenesulphonamide) metabolism in the rat.

1. Rats given a meal containing 613 p.p.m. of 14C-sulphathiazole (4-amino-N-2-thiazolyl[14C]benzenesulphonamide) excreted less 14C-activity in urine and more 14C-activity in faeces as nitrite in the meal was increased (0, 10, 100 or 1000 p.p.m.). As nitrite in the meal was increased from 0 to 1000 p.p.m. the total 14C-residues in the gastrointestinal tract six hours after dosing increased, but decreased in other tissues. 2. High nitrite in the meal resulted in increased methanol insoluble 14C-activity in the gastrointestinal tract but had little or no effect on the methanol-insoluble activity in liver and blood. 3. Conversion of 14C-sulphathiazole to 14C-desaminosulphathiazole (N-2-thiazolyl[U-14C]benzenesulphonamide) in the rat was greatly increased by nitrite in the meal.

Microcalorimetric investigations of drug-albumin interactions.

Flow microcalorimetry was used to estimate primary binding constants for drug-albumin interactions. Measurements of heat of reaction at two temperatures illustrated the danger of extrapolation for pharmacokinetic purposes of measurements made at temperatures other than 37 degrees. The method could be used to predict competition between two drugs for a single binding site. Major advantages over spectroscopic techniques included direct determinations of thermodynamic parameters, and the use of physiological concentrations of albumin.

Circular dichroic examination of the interaction of some planar acidic drugs with tryptophan-modified human serum albumin.

The single tryptophan region in human serum albumin was investigated for its involvement in binding planar hydrophobic and acidic drug molecules. The lone tryptophan was alkylated with a selective and specific agent, 2-hydroxy-5 nitrobenzyl bromide. The subsequent interaction of four drug molecules with tryptophan modified, and normal albumin was examined by circular dichroism (CD). In all cases the CD signal of tryptophan modified albumin was perturbed at low drug concentrations. The predominantly alpha-helical structure of the albumin remained intact. It is suggested that the primary binding site of these four acidic planar drugs does involve the tryptophan region.

Disposition of sulfonamides in food-producing animals: pharmacokinetics of sulfathiazole in swine.

Disposition of sulfathiazole in plasma and urine of swine was determined following single intravenous and oral doses. Pharmacokinetics of the drug were described by a 1-compartment open model. The drug was rapidly eliminated, mainly by renal excretion of unchanged sulfathiazole and metabolism to acetylsulfathiazole, with a biological half-life of 1.4 hours. Sulfathiazole (in solution) was absorbed rapidly (half-life 0.8 hour) and relatively completely (73%) following oral administration.

Binding of salicylate and sulfathiazole by whole blood constituents.

The binding of salicylic acid and sulfathiazole to bovine whole blood, plasma proteins, and purified albumin fraction was investigated using a dynamic dialysis system. The binding profiles for salicylic acid were quite similar in bovine plasma and 4% bovine serum albumin. In contrast, the binding of sulfathiazole was significantly greater in the plasma than in solutions of fraction V bovine serum albumin. Data from dynamic dialysis binding studies of the compounds, conducted in whole blood and suspended erythrocyte systems, did not lend themselves to analysis by classical methods. Hemolysis and alteration in the nature of the protein binding sites during the binding studies were shown to be factors that could explain the unusual binding observed in the whole blood system.

Application of electrophoresis for separation of trimethoprim and sulphamethoxazole in combined therapy.

Determination of the concentration of each drug in the combination trimethoprim: sulphamethoxazole was performed in patient sera by separation of the drugs by electrophoresis in agarose-gel followed by microbiological assay. The electrophoretic method was equivalent to the methods used in the routine and showed good reproducibility,