Photolysis of sulfamethoxypyridazine in various aqueous media: aerobic biodegradation and identification of photoproducts by LC-UV-MS/MS.

Sulfonamides are one of the most frequently used antibiotics worldwide. Therefore, mitigation processes such as abiotic or biotic degradation are of interest. Photodegradation and biodegradation are the potentially significant removal mechanisms for pharmaceuticals in aquatic environments. The photolysis of sulfamethoxypyridazine (SMP) using a medium pressure Hg-lamp was evaluated in three different media: Millipore water pH 6.1 (MW), effluent from sewage treatment plant pH 7.6 (STP), and buffered demineralized water pH 7.4 (BDW). Identification of transformation products (TPs) was performed by LC-UV-MS/MS. The biodegradation of SMP using two tests from the OECD series was studied: Closed Bottle test (OECD 301 D), and Manometric Respirometry test (OECD 301 F). In biodegradation tests, it was found that SMP was not readily biodegradable so it may pose a risk to the environment. The results showed that SMP was removed completely within 128 min of irradiation in the three media, and the degradation rate was different for each investigated type of water. However, dissolved organic carbon (DOC) was not removed in BDW and only little DOC removal was observed in MW and STP, thus indicating the formation of TPs. Analysis by LC-UV-MS/MS revealed new TPs formed. The hydroxylation of SMP represents the main photodegradation pathway.

[Pharmacokinetics and plasma protein binding of sulfamethoxypyridazine in camels (Camelus dromedarius)]. / Etude de la pharmacocinétique et de la liaison aux protéines plasmatiques de la sulfaméthoxypyridazine chez le dromadaire (Camelus dromedarius).

The pharmacokinetics of sulfamethoxypyridazine (SMPD) were investigated in the camel after intravenous and oral administration. After intravenous injection, the plasma concentration of the drug followed the kinetics of a two-compartment model. The steady-state volume of distribution (Vss) of 0.47 l/kg suggested that sulfamethoxypyridazine was mostly distributed within the vascular compartment and the strongly vascularized tissues. The elimination from the body was rather slow, with a biological half-life [t1/2(beta)] and a total plasma clearance of about 9.5 h and 0.037 l/kg.h, respectively. Oral treatment showed that the maximum plasma concentration was reached 17 hours post drug administration and that the bioavailability ranged around 57%. Study of the plasma protein binding showed that the percentage of SMPD binding to plasma proteins varied from 47 to 72% and seemed to be concentration-dependent. The total binding capacity and the dissociation constant at equilibrium were 196 micrograms/ml and 335 micrograms/ml, respectively.

[Characteristics of the distribution of long-acting sulfanilamides in purulent pyelonephritis in rats]. / Osobennosti raspredeleniia dlitel'no deistvuiushchikh sul'fanilamidov pri sinegnoinom pielonefrite u krys.

Distribution of sulfalen, sulfadimethoxine and sulfamethoxypyridazine in the blood and organs of rats and binding of the drugs to the blood serum proteins of the animals with experimental P. aeruginosa pyelonephritis were studied. It was shown that in rats with P. aeruginosa pyelonephritis the levels of long-acting sulfanilamides in the blood and organs were lower, while the levels of their penetration through the histohematic barriers were higher, which was partially due to the decreased binding of sulfanilamides to blood proteins.

Biological availability of sulfamethoxypyridazine and sulfisomidine polymers.

Dissolution rates and apparent solubilities of forms I, II and III of Sulfamethoxypyridazine (1) and forms I and II of sulfisomidine (2) were determined in water at 37 degrees C. The ratios of apparent solubilities of I:II:III for 1 forms and I:II for 2 forms were 1:1.18:1.25 and 1:1.32 respectively. Upon long contact of 2 with water the ratio of II:I decreased. This has been attributed to gradual transformation of 2 from form II to I. Gastrointestinal absorption of form III of 1, in human volunteers, was studied in comparison with the more stable form I. The same study was carried out on forms I and II of 2. Data were correlated and expressed in availability rate constants (K1), applying the one compartment open: model. This and other parameters show that form III of 1 is 1.4 times as much absorbed as form I, and that the availability of the metastable form II of 2 is 1.2 times as much absorbed as the stable form I.

[Sulfanilamide absorption and acetylation in rats with experimental hyperlipidemia and cellular regulation of the process of acetylation]. / Vsasyvanie i atsetilirovanie sul'fanilamidov pri éksperimental'noi giperlipidemii u krys i kletochnaia reguliatsiia protsessa atsetilirovaniia.

Experiments on an isolated ileum of the rat with experimental hyperlipidemia have shown the decreased acetylation rate of sulfalen, sulfamonomethoxin and sulfapyridazine. The absorption rate of the free forms of sulfanilamides was increased (significantly for sulfalen and sulfapyridazine). Isadrin (1 . 10(-8) M) and cAMP (1 . 10(-5) M) introduced into the liquid exposed to the mucosa of the rat ileum raised the acetylation rate of sulfamonomethoxin by the ileic wall while anaprilin (1 . 10(-6) M) led to the reduction of both absorption and acetylation of this sulfanilamide. Addition of cAMP to the incubation mixture of mitochondria and microsomes increased the acetylation rate of sulfamonomethoxin.

The effect of protein concentration on the binding of sulfamethoxypyridazine by human and bovine serum albumin.

Several methods of analyzing data obtained for ligand-macromolecule interactions at various concentrations of protein have been examined. Of the methods examined, only the constants ni, the number of binding sites of class i, and ki, the association constant for the i'th class of binding sites, were found useful in the detection of protein concentration dependent binding. The values of niki and sigma niki were calculated from previously obtained data for the interaction of sulfamethoxypyridazine with human and bovine serum albumin at seven protein concentrations. In disagreement with a previous report, the results obtained suggest that this protein-ligand interaction is either independent of protein concentration or that the protein concentration dependence of the binding constants is small relative to the experimental error involved in their determination.

The effect of protein-binding on the excretion of three sulphonamide preparations in the milk of dairy cows, examined by chemical and microbiological methods.

The relationship between the protein-binding of sulphonamides and their excretion in the milk of dairy cows was studied using three preparations commercially available in Finland. After a preparations containing sulfadiazine and sulfadimidine was given intravenously to dairy cows the drugs were excreted into milk to a greater extent than in the case of sulfamethoxypyridazine and especially of sulfaphenazole given similarly. An inverse relationship was found between the degree of protein-binding in the serum and the excretion into milk. The antimicrobially active concentrations of sulphonamides in serum and milk persisted for less than 24 hours when the doses recommended by the manufacturers were used. From a pharmacological point of view the sulfadiazine-sulfadimidine combination seems to be the drug of choice. Although no traces of sulphonamides were detected 48 hours after the dosing, the question of milk residues could not be answered because the minimum detection level of the methods used in the study was approximately 1 microgram/ml. The IDF standard method for the detection of penicillin in milk is not suitable for the detection of sulphonamide residues in milk.

Permeability of selected drugs and chemicals across the blood-testis barrier of the rat.

Physiological studies by Setchell and others have described the existence of a blood-testis barrier (BTB) surrounding the seminiferous tubules of the mammalian testis. These studies were initiated to better define the role of the BTB with regard to the penetration of exogenous chemicals to male germ cells. The rete testis was cannulated in rats and fluid was collected. Test chemicals or drugs were usually administered by continuous i.v. infusion. Permeability of nonelectrolytes of various molecular sizes, acidic compounds with varying partition coefficients and pKalpha values, such as salicylic acid, barbiturates, and sulfonamides, across the BTB were studied. Permeability of nonelectrolytes was demonstrated to be dependent upon their molecular size, suggesting bulk flow through water-filled pores. On the other hand, permeability of acidic drugs with varying pKalpha values depended upon their partition coefficients. Transport of these chemicals from blood to seminferous tubules closely resembled their transport from blood to cerebrospinal fluid. It appears that the BTB is a complex multicellular system composed of membranes surrounding the semiferous tubules and the several layers of spermatogenic cells organized within the tubules, which restrict the permeability to the male germ cells of many foreign compounds. This must be borne in mind when extra-polating data from in vitro mutagenic test systems to man.

Drug-induced change in the distribution of sulfonamides in the mother rat and its fetus.

The distribution of a highly bound antibacterial sulfonamide was markedly altered in both the mother rat and its fetus by interfering with the binding of this drug to plasma protein in the mother. This effect was due to binding displacement, since the displacing agent had little or no effect on the distribution of another sulfonamide with very low binding to plasma protein.