Sustained release of metformin via red blood cell accumulated sulfenamide prodrug.

Metformin is a first-line antidiabetic drug to treat type 2 diabetes. It is rapidly eliminated from plasma but also accumulated into red blood cells (RBCs) from which it is slowly released back into plasma. The aim of the study was to evaluate whether the amount of metformin in the RBCs could be increased by a sulfenamide prodrug approach, which could provide longer duration of metformin in systemic circulation. Pharmacokinetic properties of metformin and its cyclohexyl sulfenamide prodrug were evaluated in plasma and in whole blood after intravenous and oral administration in rats. Once the sulfenamide prodrug reached the bloodstream, it was rapidly and efficiently accumulated into the RBCs, where it was converted to metformin by free thiols. The RBC-whole blood ratio of metformin was increased approximately from 42% to 96% when metformin was administered intravenously as its sulfenamide prodrug, and the proportion of metformin in the RBCs was found to be concentration and time independent. Because metformin was slowly liberated into plasma, the prodrug showed a sustained-release pharmacokinetic profile and longer plasma half-life for metformin after oral administration. Therefore, this sulfenamide prodrug has great potential to improve metformin therapy as the daily doses could be reduced.

Oral bioavailability of sulphonamides in ruminants: a comparison between sulphamethoxazole, sulphatroxazole, and sulphamerazine, using the dwarf goat as animal model.

The various sulphonamides show marked differences in disposition characteristics after administration to ruminants. For use in combination with a diaminopyrimidine derivative such as trimethoprim or baquiloprim, it is essential that a sulphonamide has similar pharmacokinetic properties in order to obtain optimal synergy. In the present study the pharmacokinetics of sulphamethoxazole, sulphatroxazole, and sulphamerazine were investigated in dwarf goats (n = 6) after IV and intraruminal administration at a dose of 30 mg/kg bodyweight. In addition, the in vitro binding of sulphamerazine to ruminal contents was studied as a possible explanation for a reduced absorption rate. Sulphamethoxazole showed the most rapid absorption after intraruminal administration (mean tmax +/- SD : 0.8 +/- 0.2h). However, the drug was rapidly eliminated from the plasma (t1/2 beta : 2.4 +/- 1.5 h) and the bioavailability was only 12.4 +/- 4.7%, most likely due to an extensive 'first-pass' effect. The bioavailability of orally administered sulphamerazine and sulphatroxazole was much higher (67.6 +/- 13.5% and 70.2 +/- 32.3%, respectively). After intraruminal administration, sulphatroxazole showed the highest plasma peak concentration (26.1 +/- 6.3 mg/l) and the longest plasma half-life (4.7 +/- 1.8h) and mean residence time (13.9 +/- 4.5 h). Sulphamerazine showed considerable binding to rumen contents in vitro. Based on its pharmacokinetic properties sulphatroxazole appears to be a suitable candidate to be used in combination with the more recently developed diaminopyrimidines such as baquiloprim.

Pharmacokinetics and renal clearance of sulphadimidine, sulphamerazine and sulphadiazine and their N4-acetyl and hydroxy metabolites in pigs.

The effect of molecular structure on the drug disposition and protein binding in plasma, the urinary recovery, and the renal clearance of sulphamerazine (SMR), sulphadiazine (SDZ), and sulphadimidine (SDM) and their N4-acetyl and hydroxy derivatives were studied in pigs. Following IV administration of SDM, SMR and SDZ, their mean elimination half-lives were 12.4 h, 4.3 h and 4.9 h respectively. The plasma concentrations of parent sulphonamide were higher than those of the metabolites, and ran parallel. The acetylated derivatives were the main metabolites; traces of 6-hydroxymethylsulphamerazine and 4-hydroxysulphadiazine were detected in plasma. The urine recovery data showed that in pigs acetylation is the major elimination pathway of SDM, SMR and SDZ; hydroxylation became more important in case of SMR (6-hydroxymethyl and 4-hydroxy derivatives) and SDZ (4-hydroxy derivatives) than in SDM. In pigs methyl substitution of the pyrimidine side chain decreased the renal clearance of the parent drug and made the parent compound less accessible for hydroxylation. Acetylation and hydroxylation speeded up drug elimination, because their renal clearance values were higher than those of the parent drug.

[The influence of galenic and biologic factors on the bioavailability of Berlocombin]. / Der Einfluss galenischer und biologischer Faktoren auf die Bioverfügbarkeit von Berlocombin.

The analysis of the influence of galenical and biological factors on the biological availability of Berlocombin (sulfamerazin and trimethoprim combination) has been performed by a single Berlocombin juice administration compared to tablets and by a tablet administration combined with nourishment. In case of the juice administration, the biological availability of trimethoprim and sulfamerazin has been reduced. The tablet administration at an empty stomach and a subsequent 5-h waiting period revealed a more complete trimethoprim resorption, which compared to an administration immediately after the standard breakfast is expressed by a significantly greater area under the concentration-time curve (AUC) in serum. In tablet application subsequent to a fatty breakfast, the trimethoprim and sulfamerazin resorption is compared to the relative group some increased; the differences, however, were insignificant ones. The results of this study failed to be of practical consequences, because the dosage applied and recommended by the producer significantly exceeded the minimum inhibition concentrations in serum and urine 3 h after administration. The required therapeutic level in no case fell short of up to the 12. hour.

Isolation and identification of 4-hydroxysulfamerazine and preliminary studies on its pharmacokinetics in dogs.

For the following compounds: sulfamerazine, 4- hydroxysulfamerazine , N4- acetylsulfamerazine , N4-acetyl-4- hydroxysulfamerazine , the following data are reported: biosynthesis in the dog, isolation, identification by MS and NMR, TLC (Rf values) and HPLC (capacity factors and molar extinction), half-life of elimination, metabolism, renal excretion and protein binding in dog. Dogs are unable to acetylate sulfamerazine, but eliminate predominantly by hydroxylation of the N1-substituent. Administered N4- acetylsulfamerazine is predominantly eliminated by deacetylation to sulfamerazine which in turn is hydroxylated. The renal clearances of sulfamerazine and N4- acetylsulfamerazine in the dog are identical. The renal excretion of both compounds proceeds by the passive processes of glomerular filtration and tubular reabsorption. 4- Hydroxysulfamerazine and its glucuronide have a higher renal clearance than sulfamerazine.

Pharmacokinetics of sulfamerazine and antipyrine in neonatal and young lambs.

The disposition of sulfamerazine after oral and after IV administrations was studied in lambs at different times after birth. There was a gradual increase in systemic clearance and plasma binding until the 9th week. After sulfamerazine was given orally, there was a marked evolution in the shape of the concentration-time curves in function of age, strongly suggesting a defective absorption rate in the first weeks after birth. For antipyrine, too, the clearance increased gradually during the period of study, but absorption seemed to be rapid in the very young animals.

[Pharmacokinetic findings following the oral application of granulated Mebacid in cattle, calves and sheep]. / Pharmakokinetische Untersuchungsergebnisse nach oraler Applikation von Mebacidgranulat beim Rind, Kalb und schaf.

The pharmacokinetic properties of sulphamerazine, following oral application of granulated Mebacid to cattle, calf, and sheep, were compared with results obtained from the use of Mebacid tablets. Elimination half-life was higher in cattle, calf, and sheep, following oral application of Mebacid tablets. Different pharmacokinetic properties of sulphamerazine were found to exist between the two modes of preparation. Sulphonamide was eliminated more rapidly by cattle, calf, and sheep, when granulated Mebacid was used. When granulate is used, higher sulphamerazine doses have to be applied to calf and sheep to obtain the sulphonamide levels required for effective therapy. No intolerance was recorded from the above species, following oral application of granulated Mebacid.

[Pharmacokinetic model studies of sulfamerazine in domestic mammals. 3. Acetylation, protein binding, and minimal inhibitory concentration of sulfamerazine]. / Pharmakokinetische Modelluntersuchungen an Sulfamerazin bei Haussäugetieren. 3. Mitteilung: Azetylierung, Eiweissbindung und minimale Hemmkonzentration von Sulfamerazin.

Acetylation and protein fixation were established for the purpose of elucidating the chemotherapeutically effective part of sulphamerazine when applied to cattle, swine, horse, sheep, dog, and cat. The highest degree of acetylation and lowest protein fixation in all species tested, were recorded from swine. A reciprocal correlation was found to exist between the two above parameters, and it was statistically secured, except for horse. A mathematical description of the functional relationship between sulphamerazine fixed to serum protein and free sulphamerazine was possible by means of the Freundlich isothermia which had been recommended by SCHOLTAN (1962) in the following form: cgeb = K+ . cfreim The problem of minimum inhibitory concentration is discussed and explained in greater detail by computational examples with Escherichia coli.

[Pharmacokinetic model studies of sulfamerazine in domestic mammals. 1. Elimination of Mebacid 200 following intravenous administration to large animals]. / Pharmakokinetische Modelluntersuchungen an Sulfamerazin bei Haussäugetieren. 1. Mitteilung: Die Elimination von Mebacid 200 nach intravenöser Applikation beim Grosstier.

Pharmacokinetic data of sulphamerazine were recorded from eight heads each of calf, adult cattle, horse, and sheep, following intravenous application of Mebacid 200, and mathematical implications were discussed. Exponential excretion was recorded from all species, according to the following equation: c = B x e-k2 x t The most favourable pharmacokinetic parameters were recorded from calf.

[Pharmacokinetic model studies of sulfamerazine in domestic mammals. 2. Elimination of Mebacid 200 and Mebacid tablets following oral, subcutaneous and intramuscular administration]. / Pharmakokinetische Modelluntersuchungen an Sulfamerazin bei Haussäugetieren. 2. Mitteilung: Die Elimination von Mebacid 200 und Mebacid-Tabletten nach oraler, subkutaner und intramuskulärer Applikation.

The mathematical foundations underlying pharmacokinetic testing and acceptance of medicaments for domestic mammals are expounded and discussed, with reference being made to examples of intramuscular, subcutaneous, and oral application of Mebacid 200 and Mebacid tablets. Elimination of sulphamerazine may be mathematically described by means of the following bi-exponential function: c = B x e-k2 x t -- A x e-k1 x t The concepts of the mono-compartmental model "Extravasal Application" can be claimed as being of basic validity. Blood levels established after intramuscular and subcutaneous application of sulphamerazine-sodium (Mebacid 200) were lower than those recorded after oral application of Mebacid tablets. The half-lives of elimination, following oral application to big animals of Mebacid tablets, were longer than those following intravenous application of comparable injection solution.

[Pharmacokinetic studies of sulfamerazine-Na, sulfaperine-Na and sulfadimidine-Na in the hen]. / Pharmakokinetische Untersuchungen von Sulfamerazin-Na, Sulfaperin-Na und Sulfadimidin-Na beim Huhn.

The pharmacokinetic properties of sulphaperine-sodium, Mebacid 200, and sulphadimidine-sodium were experimentally established from fowl and mathematically objectivated. The highest half-life for elimination, coupled with low protein fixation, was recorded from sulphadimidine, by comparison of the above three sulphonamides. These data were used in dosage calculations for clinical testing.

Disposition of sulfonamides in food-producing animals: pharmacokinetics of sulfamerazine in ewe lambs.

Date from plasma and urine samples from four ewe lambs were analyzed after administration of sulfamerazine as single IV and oral doses. A two-compartment pharmacokinetic model was developed to describe the disposition of sulfamerazine. The drug was eliminated, primarily by renal excretion of (i) unchanged sulfamerazine and metabolism to an acetyl metabolite, (ii) polar conjugates, and (iii) a third metabolite. The biological half-life of the drug was 6.6 hours. The average value of the absorption rate constant was 0.433 hour-1 (half-life 1.60 hours). Sulfarmerazine was relatively completely absorbed (approx 81% of dose) after oral administration in solution.

Bioavailability and dissolution behavior of trisulfapyrimidine suspensions.

The bioavailability of seven commercial trisulfapyrimidine suspensions was studied in 14 adult male volunteers. Fifteen blood samples were collected over a 48-hr period following administration of a 1-g dose of each suspension. Serum was assayed for each component (sulfadiazine, sulfamerazine, and sulfamethazine) by high-pressure liquid chromatography. Analysis of variance indicated several significant differences among the seven commercial preparations with respect to Cmax Tmax, and AUC for sulfadiazine, sulfamerazine, and sulfamethazine, The in vitro behavior of each suspension was then studied by the paddle method of the Food and Drug Administration. A 0.5-ml sample was introduced into 900 ml of hydrochloric acid (2.2 x 10(-4) M) at 37 degree and dissolved using a paddle speed of 25 rpm. Samples withdrawn at 15 and 30 min were analyzed by high-pressure liquid chromatography, and the percent of sulfadiazine, sulfamerazine, and sulfamethazine was calculated. Significant correlation was obtained between an in vivo parameter (Cmax for sulfadiazine) and an in vitro parameter (percent sulfadiazine dissolved in 30 min). Results indicate that this method is suitable for the in vitro screening of trisulapyrimidine suspensions.

The distribution of sulfamerazin between plasma, cerebrospinal fluid, and bile in humans.

The concentration-time curves of sulfamerazin were determined in plasma, cerebrospinal fluid (c.s.f.) and bile in two groups of patients (ventricle drainage and Kerr's T-tube drain). In plasma, a half-life of 13.6 hours as well as an invasion and evasion constant of 0.145 hours -1 and 0.051 hours -1, resepectively, were observed. The distribution of half-life times showed a bimodal behavior in these patients. The unbound part of sulfamerazin was 12% and the acetylated products 14%. Unlike plasma in c.s.f. and bile the influx is delayed up to steady state. The decreases of concentration in all three compartments are the same. The concentration ratio of sulfamerazin between C.S.F. and bile and plasma water amounted to 1 and 2.5, respectively. Of the given dose of sulfamerzin, 0.87% was eliminated by bile within 24 hours. The therapeutic conclusions are discussed with regard to the bimodal distribution of half-lives, the minimal inhibition concentrations and the unbound part in the plasma.

Simple high-pressure liquid chromatographic determination of trisulfapyrimidines in human serum.

A simple and rapid high-pressure liquid chromatographic method was developed for the determination of sulfadiazine, sulfamerazine, and sulfamethazine in human serum. After the trichloroacetic acid precipitation of the serum proteins, an aliquot of the supernate is injected into a high-pressure liquid chromatograph equipped with a reversed-phase microparticulate column and a fixed wavelength UV detector. For each of the three components of trisulfapyrimidines, a linear calibration curve was observed in the 1-30-microgram/ml range, with the precision of the assay estimated to be +/- 2% (RSD). Preliminary pharmacokinetic data are also presented.

Half-life, apparent volume of distribution and protein-binding for some sulphonamides in cows.

The half-lives, apparent volume of distribution and protein-binding of 11 sulphonamides were determined in 89 experiments on 49 cows. The estimations of half-lives indicated the presence of a distribution phase (alpha-phase) for all the sulphonamides investigated with the exception of sulphachloropyridazine. The elimination half-life (beta-phase) of the sulphonamides in plasma varied from 70 to 1000 min and was positively correlated with the solubility of the compounds in organic solvents. This was explained by the greater reabsorption of the more fat-soluble compounds in the kidneys. All the sulphonamides except sulphadimidine had a shorter half-life in cows than previously reported from human investigations. The apparent volume of distribution was about one for sulphanilamide and lower for all the other sulphonamides investigated. The protein-binding estimated in vitro agreed well with the in vivo results. It was slightly lower than in humans and the degree of protein-binding decreased with increasing sulphonamide concentration in plasma.