An amide-based sulfenamide prodrug of gamma secretase inhibitor BMS-708163 delivers parent drug from an oral conventional solid dosage form in male beagle dog.

The objective of this Letter is to report the first (to our knowledge) in vivo proof of concept for a sulfenamide prodrug to orally deliver a poorly soluble drug containing a weakly-acidic NH-acid from a conventional solid dosage formulation. This proof of concept was established using BMS-708163 (1), a gamma secretase inhibitor containing a weakly acidic primary amide NH-acid as the chemical handle for attaching a series of thiol-based promoieties via a sulfenamide linkage. Aqueous stabilities and solubilities are reported for a series of six sulfenamide prodrugs (2-7) of 1. The sulfenamide prodrug containing the cysteine methyl ester promoiety (5) was chosen for a orally-dosed PK study in male beagle dog comparing a solubilized formulation of 1 against a solid dosage form of 5 in a cross-over fashion at an equivalent molar dose of 3 mg/kg. Prodrug 5 delivered essentially a superimposable PK profile of 1 compared to the solubilized formulation of 1, without any detectable exposure of 5 in systemic circulation.

Elucidation of the role of hydrophobic bonding in influencing intestinal absorption of model sulfonamides and revealing possible mechanism of drug absorption in rat model.

A recirculation technique was used to study the first-order kinetics of intestinal absorption of un-ionized sulfadiazine, sulfamerazine, and sulfamethazine in rats in situ at 32, 35, and 38 degrees C. The absorption rate constant (Kab) of each sulfonamide increased with increase in temperature and, at each temperature, Kab was the highest for sulfamethazine and the lowest for sulfadiazine. Applying the activated complex formation theory, the energy of activation (Ea), free energy of activation (delta F*), enthalpy of activation (delta H*), and entropy of activation (delta S*) of absorption were determined for the sulfonamides to gain some insight into the mechanism of their intestinal absorption. The high values of delta F* indicated that the barrier for sulfonamide absorption was great. For each drug, the value of delta H* was positive and that the delta S* negative. However, delta H* and delta S* were the highest for sulfamethazine and the lowest for sulfadiazine, thus revealing the influence of hydrophobic bonding in increasing Kab of the sulfonamides with the increase in methyl group content of their molecules. By considering the facts that (1) the microvillus membrane of the intestinal absorptive cells regulates the rate of passive absorption of drugs, (2) the microvillus membrane is rich in proteins, which are located external to the membrane and exposed to the intestinal fluid, and (3) hydrophobic bonding contributes to the activation parameters of absorption, it was postulated that the activated complex formed in the absorption process consisted of a transient association of the sulfonamide molecules with some protein component of the microvillus membrane.

Pharmacokinetics, metabolism, and renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy metabolites in calves and cows.

The effect of molecular structure on the drug disposition and protein binding in plasma and milk, the urinary recovery, and the renal clearance of sulfadiazine, sulfamerazine, and sulfamethazine and of their N4-acetyl and hydroxy derivatives were studied in calves and cows. Sulfadiazine was highly acetylated and was slightly hydroxylated. Sulfamerazine and sulfamethazine were hydroxylated predominantly at the methyl group of the pyrimidine side chain; hydroxylation of the pyrimidine ring itself was more extensive for sulfamethazine than for sulfamerazine. At dosages between 100 and 200 mg/kg of body weight, sulfamethazine had a capacity-limited elimination pattern, which was not observed for sulfadiazine or sulfamerazine. The concentrations of the parent sulfonamide and its metabolites in plasma and milk were parallel, the latter being lower. Metabolite concentrations in milk were at least 8 times lower than those of the parent drug. Metabolism speeds drug elimination, producing compounds with renal clearance values higher than those of the parent drug. The effect on the metabolism and renal clearance of methyl substitution in the pyrimidine side chain is discussed.

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.

[Pharmacokinetics of sulfamerazine after a single intravenous dose in healthy calves and calves with diarrhea of different severity with consideration of the influence of an existing kidney function restriction]. / Pharmakokinetik von Sulfamerazin nach einmaliger intravenöser Applikation bei gesunden und unterschiedlich stark durchfallkranken Kälbern unter Berücksichtigung des Einflusses einer vorhandenen Nierenfunktionseinschränkung.

Blood levels of Sulfamerazine were examined in 16 calves with different severity of diarrhoea in consideration of kidney function and compared with the values of 5 clinically intact animals. Urea and creatinine levels in plasma as well as urea and creatine clearance were tested to check kidney function. A single dose of 60 mg Sulfamerazine/kg body weight was administered to all animals via catheter into the vena jugularis. Blood samples were collected for 48 hours. The mean concentration of Sulfamerazine in calves with severe diarrhoea was significantly higher 24 hours post application than in the healthy control group and in animals with low and middle intensive diarrhoea (healthy animals: 37.61 +/- 7.18 micrograms/ml; animals with severe diarrhoea: 57.3 +/- 7.5 micrograms/ml). Animals with severe diarrhoea showed significantly higher values of half life time of elimination t1/2 (healthy animals: 7.08 +/- 1.25 h; animals with severe diarrhoea: 11.39 +/- 2.11 h) and of area under the curve AUC (healthy animals: 2023.4 +/- 397.21 micrograms*h/ml; animals with severe diarrhoea: 2990.6 +/- 594.9 micrograms*h/ml) than the others. Low and middle intensive diarrhoea has no important influence on the pharmacokinetics of Sulfamerazine.

In vitro conversion of model sulfenamide prodrugs in the presence of small molecule thiols.

Sulfenamide prodrugs of amide and urea functional group containing drugs have recently been proposed as a means of altering the physical and bioproperties of problematic drug molecules containing these two functionalities. Sulfenamides have been shown to revert to the parent drug via reaction with thiols. Explored here is the mechanism for this reaction. The stoichiometry and pH dependency of the in vitro reversion of two model prodrugs of the oxazolidinone, linezolid, and a sulfenamide of phthalimide were studied at 25 °C in the presence of thiols, including cysteine and glutathione, of varying basicity. High-performance/pressure liquid chromatography and liquid chromatography-mass spectrometry results showed the near quantitative reversion of the sulfenamides to the parent drug with simultaneous formation of a mixed disulfide. The pH and the dependency of the reaction on the basicity of the thiol strongly supported the role of the thiolate species in the conversion. The reaction is consistent with an S(N)2 type mechanism seen in the reaction of some thiols with disulfides.