Plasma disposition of sulfadimidine (SDM) and its metabolites was studied in laying hens after 100 mg SDM kg-1 doses were administered as a single intravenous dose, a single oral dose and multiple oral doses once daily for five consecutive days. SDM was extensively metabolized by acetylation and hydroxylation. In plasma, the metabolite observed with the highest concentration was N4-acetylsulfadimidine (N4-SDM) followed by hydroxymethylsulfadimidine (CH2OH) and 5-hydroxysulfadimidine. Following intravenous administration a biphasic elimination (as seen for a capacity limited reaction) pattern for SDM and its metabolites was observed. Multiple (5x) SDM dosing revealed plasma SDM concentrations ranging between 7 and 108 ug mL-1; within 96 hours of termination of the multiple SDM dosing, the plasma SDM concentration was below 0.01 ug mL-1. The renal clearances of N4-SDM and the hydroxy metabolites were approximately 10 times greater than that of SDM. The SDM mass balance (fecal/urinary recovery) showed a loss of 56 per cent after intravenous dosage and of 67 per cent after a single oral dosage; the hydroxy metabolites accounted for the highest percentage in feces/urine. Thus additional metabolic pathways must exist in laying hens.
After 10 male and two female healthy volunteers were given oral doses of sulfamethazine of 12-17 mg/kg bw, 10-20% of the dose was excreted in the urine as free and conjugated hydroxylated metabolites and 61-81% as N4-acetylsulfamethazine. Six of the individuals were considered to be fast acetylators and six slow acetylators. The plasma concentration-time curve for sulfamethazine in the fast acetylators was biphasic, with half-times of 1.7 and 5.4 hr, respectively, whereas in the slow acetylators it was monophasic, with a half-time of 7.6 hr.
Sulfamethazine is metabolized similarly in animals and humans, with N4-acetylation dominating. A trimodal pattern of sulfamethazine acetylation is seen in humans. Differences in acetylation rates were observed between male and female rats and among females of different strains.
The pharmacokinetics of sulfamethizole, sulfamethoxazole, sulfadiazine, sulfapyridine and sulfadimidine have been studied in man. Renal clearance values of the metabolite N4-acetylsulphonamide are 6 to 20 times higher than those of the corresponding parent compound. The renal clearance of sulfonamides is dependent on the urine flow. N4-Acetylsulfonamide concentration-time profiles for plasma and urine have been constructed for the sulfonamides. The percentage N4-acetylsulfonamide-time profiles for plasma are excellent tools for establishing the acetylator phenotype, while those constructed from urine samples are less useful. Evidence is obtained that sulfadimidine is metabolically processes by 2 different isoenzymes, while sulfadiazine, sulfapyridine and sulfamethoxazole are processes by 1 acetylating isoenzyme. Sulfamethizole is acetylated to very little extent.
IDENTIFICATION AND USE: Sulfamethazine (SMZ) is a creamy-white powder or crystals. It is anti-infective agent used in veterinary medicine. Sulfamethazine is used as a broad-spectrum antimicrobial to treat or prevent infections caused by susceptible organisms. Infections treated may include pneumonia, intestinal infections (especially coccidia), soft tissue infections and urinary tract infections. HUMAN EXPOSURE AND TOXICITY: Sulfamethazine did not induce unscheduled DNA synthesis in human fibroblasts in culture. ANIMAL STUDIES: In rats fed diets containing 600 mg/kg sulfadimidine, hyperplasia and limited hypertrophy of thyroid were seen in some rats at weeks 4 and 8 but not at week 13. There was complete recovery of the changes noted in the thyroid after the recovery period. Absolute and relative thyroid weights increased significantly in normal rats consuming diets containing 2400 and 4800 mg sulfadimidine/kg feed. In the hypophysectomized rats, relative thyroid weights tended to be slightly less than those of normal controls, but no effects of sulfadimidine treatment were found. Follicular-cell hypertrophy and hyperplasia were observed in normal sulfadimidine-treated rats. Hypophysectomized rats (with no TSH) administered SMZ did not develop morphologic changes in the thyroid. Sulfamethazine did not increase thyroid cell proliferation in vitro in the absence of TSH and there was no effect on thyroid structure/function in cynomolgus monkeys administered sulfamethazine. Nonhuman primates and human beings are known to be more resistant than rodents to the inhibition of thyroperoxidase. Female mice were fed either a control diet or a diet containing 300, 600, 1200, 2400 or 3600 mg/kg sulfamethazine for 90 days. In the mice, no treatment-related lesions were seen grossly or by light microscopy. The incidence of thyroid tumors was increased in both male and female mice after 2 yr in the high-dose (4800 ppm) group but not in the lower-dose groups. Rats were given 10, 40, 600, 1200 or 2400 ppm SMZ in the diet to determine the toxicity and potential carcinogenicity of SMZ. A statistically significant dose-related increase in the incidence of follicular cell adenocarcinomas of the thyroid gland was observed in the animals killed after 24 months. The incidences of non-neoplastic lesions of the thyroid gland in treated animals were significantly higher among treated animals than among controls; these lesions included follicular cell hyperplasia, follicular cell focal cellular change and multilocular cysts. The incidences of retinal atrophy, atrophy of the acinar pancreas (males) also increased with increasing SMZ dose. In several avian species exposure to SMZ results in plasma elevation of gonadotropins and prolactin. No treatment-related histopathological effects were observed in the pituitary or reproductive organs of male or female mice in the group fed 1% sulfamethazine. Rats were dosed by gavage with 0, 540, 680, or 860 mg sulfadimidine/kg bw/day on days 6-15 of gestation. Maternal body-weight gain was decreased and relative liver weight was increased in all treated dams. In the high-dose group, fetuses had decreased body weights and the number of malformed fetuses/litter was increased. The incidence of gross or visceral malformations of fetuses/litter was increased with the predominant malformations being cleft palate, hydroureter, and hydronephrosis. The incidence of hydroureter and hydronephrosis was also elevated in the mid-dose group. Sulfamethazine was tested for mutagenicity in the Salmonella/microsome preincubation assay in 5 Salmonella typhimurium strains (TA 1535, TA 1537, TA 97, TA 98, and TA 100) in the presence and absence of metabolic activation. Sulfamethazine was negative in these tests and the highest ineffective dose tested was 1000 ug/plate (1.0 mg/plate).
Evaluation: There is inadequate evidence in humans for the carcinogenicity of sulfamethazine. There is sufficient evidence in experimental animals for the carcinogenicity of sulfamethazine. Overall evaluation: Sulfamethazine is not classifiable as to its carcinogenicity to humans (Group 3). Sulfamethazine produces thyroid tumors in mice and rats by a non-genotoxic mechanism, which involves inhibition of thyroid peroxidase resulting in alterations in thyroid hormone concn and incr secretion of thyroid stimulating hormone. Consequently, sulfamethazine would be expected not to be carcinogenic to humans exposed to doses that do not alter thyroid hormone homeostasis. Evidence from epidemiological studies and from toxicological studies in experimental animals provide compelling evidence that rodents are substantially more sensitive than humans to the development of thyroid tumors in response to thyroid hormone imbalance.
The pharmacokinetics and metabolism of sulfadimidine (SDM) following intravenous administration of 100 mg/kg were studied in seven dwarf preruminant kids at 12 weeks of age, and again at the ruminant stage, when the animals were 18 weeks old. The persistence of SDM in 18-week-old kids was prolonged in comparison to the 12-week-old animals: a lower total body clearance and a prolonged elimination of SDM were obtained in the older animals. The renal clearance values of SDM and its metabolites were the same at both ages. The decrease of SDM clearance is related to the significant reduction in SDM hydroxylation at the older age. The reduced oxidative hepatic metabolism may result from the sexual maturation of the kids.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
磺胺二甲嘧啶乙酰化表型在19名健康成年人（年龄17-46岁；15名男性，4名女性；9名白人，9名东方人，1名黑人）中进行了测定，他们单次口服了20 mg/kg体重的磺胺二甲嘧啶，溶于200毫升水中。结果显示，乙酰化清除率和整体消除或代谢速率常数呈现出明确的三角模式，并确认快速乙酰化表型可以细分为中间型和快速型乙酰化组。快速乙酰化者的平均乙酰化清除率（1.34 mL/min per kg bw）是慢速乙酰化者估计清除率（0.15 mL/min per kg bw）的8.8倍，是中间型乙酰化者（0.75 mL/min per kg bw）的1.8倍。在72小时内，快速乙酰化者、中间型乙酰化者和慢速乙酰化者尿液中以乙酰磺胺二甲嘧啶形式排泄的吸收剂量的百分比平均值分别为93.7、87.7和65.6。
Sulfamethazine acetylation phenotypes were determined in 19 healthy adults (aged 17-46 years; 15 men, four women; nine white, nine oriental, one black) given a single oral dose of 20 mg/kg bw sulfamethazine in 200 mL of water. The results showed a welldefined trimodal pattern for acetylation clearance and for overall elimination or metabolic rate constants and confirmed that the fast acetylator phenotype can be subdivided into intermediate and rapid acetylator groups. The average acetylation clearance rate for rapid acetylators (1.34 mL/min per kg bw) was 8.8 times the estimated clearance for slow acetylators (0.15 mL/min per kg bw) and 1.8 times that for intermediate acetylators (0.75 mL/min per kg bw). The average percentage of an absorbed dose excreted as acetylsulfamethazine in 72-hr urine was 93.7 for rapid acetylators, 87.7 for intermediate acetylators and 65.6 for slow acetylators.
The depletion of sulfadimidine (SDM) and its N4-acetyl and hydroxy metabolites was studied in eggs laid by hens after administration of either a single or multiple oral dosages of 100 mg SDM/kg. During medication and until 1 day after the last dose, the SDM and its metabolite concentrations in the egg white exceeded those in the egg yolk and reflected the plasma levels. In the period starting 2 days after the (last) dosage, the SDM concentration in the yolk became higher than in the egg white, and the drug depletion curves ran parallel. The mean maximum amount of SDM found in the whole egg was 1500 micrograms after a single and 1280 ug after multiple dosage. In eggs, traces of the N4-acetyl and 6-methylhydroxy metabolites could be detected (mainly in the egg white), and their concentrations were approximately 40 times lower than those of the parent drug. A highly significant correlation (P less than 0.005) was found between the development stage of the oocyte at the time of (last) medication and the amount of SDM found in the egg that developed from it. A period of 7 or 8 days after the (last) dosage of 100 mg SDM/kg/day is required to obtain SDM levels below 0.1 ug/g egg.
Differential inhibitory effects of phenytoin, diclofenac, phenylbutazone and a series of sulfonam ides on hepatic cytochrom e P4502C activityin vitro, and correlation with som e m olecular descriptors in the dwarf goat (Caprus hircus aegagrus).
摘要：
The aim of the present study was to investigate the potency of various sulfonamides to inhibit tolbutamide hydroxylation (a CYP2C activity) in hepatic microsomal fractions and hepatocytes of the dwarf goat. Also a number of suggested substrates for human CYP2C9 was investigated.2. From Dixon plots (microsomal fractions) if was observed that all compounds were competitive inhibitors of tolbutamide hydroxylation. Phenytoin (PT) showed the lowest K-i. K-i for the sulfonamides ranged between 205 and 4546 mu m, sulfadoxine having the lowest K-i followed by sulfadimethoxine, sulfamoxole, sulfadimidine and sulfaphenazole.3. In hepatocytes sulfaphenazole and diclofenac were the most potent inhibitors.4. Out data indicate that PT, diclofenac (DF) and phenylbutazone (PBZ) are relative strong competitive inhibitors of tolbutamide hydroxylation and they are probably also substrates for the same enzyme. Differential inhibition of tolbutamide hydroxylation by sulfonamides was observed.5. Correlation of structural parameters with the inhibition constant or the inhibition in hepatocytes showed that molecular volume, polarisability and molecular surface area are important parameters in determining the rate of inhibition of tolbutamide hydroxylation by sulfonamides in both microsomes and hepatocytes. In addition, log P-oct are also involved in determining inhibition constants in microsomal fractions.
Arenesulfonyl Fluoride Synthesis via Copper-Catalyzed Fluorosulfonylation of Arenediazonium Salts
作者：Yongan Liu、Donghai Yu、Yong Guo、Ji-Chang Xiao、Qing-Yun Chen、Chao Liu
DOI：10.1021/acs.orglett.0c00484
日期：2020.3.20
We report herein a general and practical copper-catalyzed fluorosulfonylation reaction of a wide range of abundant arenediazonium salts to smoothly prepare various arenesulfonylfluorides using the 1,4-diazabicyclo[2.2.2]octane-bis(sulfur dioxide) adduct as a convenient sulfonyl source in combination with KHF2 as an ideal fluorine source and without the need for additional oxidants. Interestingly,
The present application provides compounds of formula: Methods of using these compounds for killing bacterial growth and treating bacterial infections are also provided.
本申请提供了以下化合物的公式：还提供了使用这些化合物杀灭细菌生长和治疗细菌感染的方法。
[EN] CONTROLLED DRUG RELEASE FROM SOLID SUPPORTS<br/>[FR] SUPPORTS SOLIDES POUR LA LIBÉRATION CONTRÔLÉE DE MÉDICAMENTS
申请人：PROLYNX LLC
公开号：WO2011140392A1
公开（公告）日：2011-11-10
The invention relates to solid supports useful in medical applications that provide controlled release of drugs, such as peptides, nucleic acids and small molecules. The drugs are covalently coupled to the solid support through a linkage that releases the drug or a prodrug through controlled beta elimination.
[EN] CONTROLLED RELEASE FROM MACROMOLECULAR CONJUGATES<br/>[FR] LIBÉRATION CONTRÔLÉE À PARTIR DE CONJUGUÉS MACROMOLÉCULAIRES
申请人：PROLYNX LLC
公开号：WO2011140393A1
公开（公告）日：2011-11-10
The invention relates to conjugates of macromolecular carriers and drugs comprising linkers that release the drug or a prodrug through rate-controlled beta-elimination, and methods of making and using the conjugates.
