The metabolism of furosemide occurs mainly in the kidneys and the liver, to a smaller extent. The kidneys are responsible for about 85% of total furosemide total clearance, where about 40% involves biotransformation. Two major metabolites of furosemide are furosemide glucuronide, which is pharmacologically active, and saluamine (CSA) or 4-chloro-5-sulfamoylanthranilic acid.
It would appear that frusemide glucuronide is the only or at least the major biotransformation metabolite in man. 2-amino-4- chloro-5-sulfamoylanthranilic acid has been reported in some studies but not in others; and is thought to be an analytical artifact.
来源:Hazardous Substances Data Bank (HSDB)
代谢
在肾功能正常的患者中，少量的呋塞米在肝脏中代谢为脱呋喃衍生物，4-氯-5-磺酰胺基安替比林酸。
In patients with normal renal function, a small amount of furosemide is metabolized in the liver to the defurfurylated derivative, 4-chloro-5-sulfamoylanthranilic acid. ...
IDENTIFICATION AND USE: Furosemide is white or slightly yellow, solid powder or crystals. Furosemide is used to treat edema associated with many diseases (either as the sole drug or as an adjunct to other antihypertensives). HUMAN STUDIES: Overdoses of diuretics are uncommon and infrequently serious. Problems most frequently involve chronic over medication or poor monitoring and/or lack of anticipation of drug interactions or not compensating for concomitant hepatic or renal dysfunction. Main toxic effects are on the kidneys with diuresis of water, sodium, and potassium leading most frequently to a hyponatremic, hypokalemic, and hypochloremic dehydration. More caution is warranted with patients at higher risk for abnormal renal function including patients with any renal disease, diabetes mellitis, and borderline fluid and/or electrolyte status. In a hospital-based study of adverse reactions to medications there was a 21% rate of adverse affects to frusemide with most common ones being hypovolemia, hyperuricemia, and hypokalemia which for the most part were mild, but the rate and severity increased with increasing daily doses. Hypersensitivity reactions such as rash, photosensitivity, thrombocytopenia, and pancreatitis are rare. Life threatening hyperkalemia and reversible renal failure occurred in an elderly male taking captopril concomitantly with furosemide. Acute rhabdomyolysis and myoglobinuria due to hypokalaemia occurred in a 74-year-old male taking furosemide. Severe anaphylactic reaction to furosemide involving urticaria; angioedema and hypotension occurred in an adult 5 minutes after receiving intravenous furosemide. Furosemide abuse (400 mg daily) was associated with severe hyponatremia and central pontine myelinolysis. Self-administration of furosemide over 6 years resulted in calcification of the renal medulla. Nephrocalcinosis and nephrolithiasis occurred in 5 children after treatment with furosemide. It has also reported nephrocalcinosis in premature infants being treated with furosemide. Cholelithiasis in infants was caused by furosemide. Tachycardia was reported following a high dose intravenous regimen using furosemide. Renal calcifications were encountered in premature infants when given furosemide. Furosemide-induced renal calcifications in low birth weight infants may lead to glomerular and tubular dysfunction in the long-term. A concentration-dependent increase in the frequency of chromosomal aberrations was observed in human lymphocytes exposed in vitro to furosemide for 24 and 72 hr. No such effect was detected in the human fibroblast cell line. ANIMAL STUDIES: Chronic administration to rats has caused tubular degeneration in the kidneys. Calcification and damage to the renal parenchyma occurred in a subchronic study in dogs. Developmental studies have been conducted in mice, rats and rabbits. An increase in the incidence and severity of hydronephrosis (distention of the renal pelvis and occasionally the ureters) was seen in a mouse study and one of three rabbit studies. In male mice treated intraperitoneally with furosemide at 0.3-50 mg/kg bw, a non-dose-dependent increase in the percentage of meiotic cells with chromosomal aberrations was observed during the whole spermatogenic cycle. Furosemide was tested over a wide range of doses (0, 100, 333, 1000, 3333, and 10,000 ug/plate) in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) with and without metabolic activation. Furosemide was negative in these tests and the highest ineffective dose level tested in any Salmonella tester strain was 10,000 ug/plate. Furosemide was reported to induce mutations in L5178Y mouse lymphoma cells in the presence of an exogenous metabolic system only at the highest concentration tested (1500 ug/mL). It was also reported to induce sister chromatid exchange and chromosomal aberrations in Chinese hamster CHO cells at 3750 and 500 ug/mL in the presence and absence of an exogenous metabolic system. Furosemide induced chromosomal damage in Chinese hamster lung fibroblasts in vitro, but only in the absence of an exogenous metabolic system. ECOTOXICITY STUDIES: Furosemide in combination with other drugs found in waste water was genotoxic to zebrafish, and exhibited toxic effects on riverine microbial communities.
Following oral administration, furosemide is absorbed from the gastrointestinal tract. It displays variable bioavailability from oral dosage forms, ranging from 10 to 90%. The oral bioavailability of furosemide from oral tablets or oral solution is about 64% and 60%, respectively, of that from an intravenous injection of the drug.
The kidneys are responsible for 85% of total furosemide total clearance, where about 43% of the drug undergoes renal excretion. Significantly more furosemide is excreted in urine following the I.V. injection than after the tablet or oral solution. Approximately 50% of the furosemide load is excreted unchanged in urine, and the rest is metabolized into glucuronide in the kidney.
The volume of distribution following intravenous administration of 40 mg furosemide were 0.181 L/kg in healthy subjects and 0.140 L/kg in patients with heart failure.
Following intravenous administration of 400 mg furosemide, the plasma clearance was 1.23 mL/kg/min in patients with heart failure and 2.34 mL/kg/min in healthy subjects, respectively.
Significantly more furosemide is excreted in urine following the IV injection than after the tablet or oral solution. There are no significant differences between the two oral formulations in the amount of unchanged drug excreted in urine.
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
[EN] SUBSTITUTED 4-PYRIDONES AND THEIR USE AS INHIBITORS OF NEUTROPHIL ELASTASE ACTIVITY<br/>[FR] 4-PYRIDONES SUBSTITUÉES ET LEUR UTILISATION COMME INHIBITEURS DE L'ACTIVITÉ DE L'ÉLASTASE NEUTROPHILE
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014029831A1
公开（公告）日：2014-02-27
This invention relates to substituted 4-pyridones of formula 1 and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other auto-immune and allergic disorders, allograft rejection, and oncological diseases.
SUBSTITUTED 4-PYRIDONES AND THEIR USE AS INHIBITORS OF NEUTROPHIL ELASTASE ACTIVITY
申请人：OOST Thorsten
公开号：US20140057916A1
公开（公告）日：2014-02-27
This invention relates to substituted 4-pyridones of formula 1
and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other auto-immune and allergic disorders, allograft rejection, and oncological diseases.
1-Amino 1H-imidazoquinoline compounds, pharmaceutical compositions containing the compounds, intermediates, and methods of making and methods of use of these compounds as immunomodulators, for modulating cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.
SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
申请人：BLUM Andreas
公开号：US20140135309A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I
wherein Ar, R
1
and R
2
are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
