AFTER NITROFURANTOIN (50 MG) IV INFUSION, 47% OF THE DOSE WAS EXCRETED UNCHANGED IN THE URINE AND 1.2% WAS RECOVERED AS THE REDUCED METABOLITE AMINOFURANTOIN.
来源:Hazardous Substances Data Bank (HSDB)
代谢
硝基呋喃妥因部分在肝脏代谢。一小部分药物还原形成氨基呋喃妥因。
Nitrofurantoin is partially metabolized, mainly in the liver. A small fraction of the drug is reduced to form aminofurantoin.
IDENTIFICATION: Nitrofurantoin is an urninary antiseptic and antiinfective drug. It is a lemon yellow solid crystalline material. It is very sightly soluble in water and alcohol. It is soluble in diethylformamide. In the treatment of initial or recurrent urinary tract infections caused by susceptible gram positive and gram negative bacteria including most strains of Escherischia coli. Enterobacter and Klebsiella species are less susceptible and Pseudomonas and most strains of Proteus are resistant to nitrofurantoin. Nitrofurantoin is ineffective in systemic bacterial infections in blood or tissues outside the urinary tract. HUMAN EXPOSURE: Main risks and target organs: The most frequent adverse effects include anorexia, nausea and vomiting. Nitrofurantoin has also been associated with neurological and central nervous system, hepatic, hematological, pulmonary and dermatological toxicity. Apart from gastrointestinal tract symptoms, acute reactions as a result of overdosage of nitrofurantoin have not been reported. Symptoms of toxicity are generally due to hypersensitivity to the drug. Contraindications: Nitrofurantoin is contraindicated in patients who are hypersensitive to the drug or to furan derivatives. It is also relatively contraindicated in renal impairment, diabetes mellitus, electrolyte imbalance, vit.B deficiency as there is an increased risk of developing peripheral neuropathy in these situations. If it has to be used in these cases, extreme care should be taken and treatment stopped at the first sign of toxicity. Hemolysis frequently occurs in Glucose-6-phosphate dehydrogenase deficient patients who take nitrofurantoin. Discontinuation of the drug will often reverse this effect. Nitrofurantoin is contraindicated in pregnant women at term (38-42 weeks gestation) and it should not be administered during labor or just prior to labor to avoid precipitation of hemolytic anemia in the neonate. Neonates are at high risk of hemolysis induced by nitrofurantoin due to their immature enzyme systems. Routes of exposure: Oral: This is the most common route of entry. Absorption by route of exposure: Nitrofurantoin is readily absorbed from the gastrointestinal tract. Absorption occurs mainly in the small intestine. The microcrystalline form of the drug (in suspension, tablets or capsules) is absorbed faster than the macrocrystalline form (in capsules). Presence of food in the gastrointestinal tract or delayed gastric emptying increases the extent of absorption (enhancing the dissolution rate of the drug). Bioavailability is a mean of 87% when taken on an empty stomach, and increases to a mean of 94% when ingested with food. Peak plasma concentrations following a single oral dose are usually attained at 1 to 2 hours after ingestion. Distribution by route of exposure: Nitrofurantoin is 25 to 90% bound to plasma protein. It crosses the placenta and is excreted in the milk. Biological half-life by route of exposure: The plasma half life is approximately 20 to 60 minutes in adults with normal renal function after a therapeutic oral dose. The half-life is prolonged in patients with impaired renal function. Metabolism: Approximately 2/3 of a dose is metabolized in the liver. A small fraction is reduced to aminofurantoin. Elimination by route of exposure: 20 to 44% of an oral dose is excreted unchanged in the urine within 24 hours. 1% is excreted as aminofurantoin. Nitrofurantoin is dialyzable. Mode of action: Toxicodynamics: Nitrofurantoin causes hepatic injury (acute and chronic) through an immunological or metabolic mechanism. Cholestatic jaundice and hepatocellular damage result in elevation of alkaline phosphatase and aspartate transaminase levels. Development of antinuclear antibodies and antismooth muscle antibodies has also been reported. Pulmonary toxicity is attributed to nitrofurantoin production of superoxide anion free radicals with subsequent chain reactions and uncontrolled destructive oxidation, suggested that nitrofurantoin mediated oxidant injury to the lung may be due to direct cytotoxicity or indirectly through recruitment of activated neutrophils. Nitrofurantoin can cause an acute non-cardiogenic pulmonary edema, or subacute interstitial pneumonitis which may progress to interstitial fibrosis. The acute reaction is generally considered to be a hypersensitivity reaction. There is evidence pointing to an immunological mechanism for injury and an increase in T-Lymphocytes in broncheo-alveolar lavage. Peripheral neuropathy is a complication of nitrofurantoin therapy especially in patients with pre-existing renal impairment or diabetes mellitus. Nitrofurantoin triggers a degenerative process in the nerve cell axon with subsequent impairment of sensation and motor strength in the distal extent of the axonal process. Pharmacodynamics: Nitrofurantoin is bacteriostatic or bacteriocidal depending on the concentration and the susceptibility of the microorganism. Its antibacterial activity is enhanced in an acidic pH. It is thought that nitrofurantoin is reduced by bacterial flavoprotein enzymes to an active intermediate which inhibits the microorganism's proteins, DNA, RNA and cell wall synthesis. Nitrofurantoin is active against most strains of Gram positive and Gram negative urinary tract pathogens but generally less active against most strains of Klebsiella, Enterobacter, Pseudomonas and Proteus. Toxicity: Human data: Adults: Acute toxic exposures to nitrofurantoin have not been reported and there have been no acute ingestions causing fatalities. No toxic or lethal levels have been determined for nitrofurantoin. However there are a number of adverse effects and hypersensitivity reactions reported which have included fatalities. The duration of exposure before the onset of symptoms of acute pulmonary toxicity varies from two or three days to several weeks. Teratogenicity: case of a 14 month old girl with asymmetrical paralysis limited to the upper limbs with signs suggesting an early prenatal onset was reported. Nitrofurantoin and Bendectin (R) taken during early pregnancy were suspected to be the cause. Mutagenicity: There are data demonstrating mutagenicity in human cells Interactions: Food significantly enhances the bioavailability and duration of the therapeutic concentration of nitrofurantoin. Uricosuric agents (probenecid or sulfinpyrazone) may inhibit renal excretion of nitrofurantoin and hence increase its plasma level, reduce its effectiveness, and increase its toxicity. Antacids: specifically magnesium trisilicate were reported to decrease the rate and extent of nitrofurantoin absorption through an adsorption mechanism. Quinolones antibacterial activity in vitro is antagonized by nitrofurantoin. It is possible that this interaction could occur in vivo as well. Drugs which acidify the urine decrease the excretion of nitrofurantoin. Main adverse effects: The most frequent adverse effects of nitrofurantoin are anorexia, nausea, and vomiting, which are dose related. Peripheral polyneuropathy and optic neuritis are serious adverse effects of nitrofurantoin and call for immediate withdrawal of the drug. They occur especially in pre-existing renal impairment and the presence of vitamin B deficiency. Peripheral neuropathy was reported in 10 month to 18 year old children. Hepatic damage with nitrofurantoin is reversible on discontinuation of the drug. Hepatic reactions range from acute self-limiting hepatitis to chronic active hepatitis and necrosis associated with long term use. Pulmonary hypersensitivity reactions to nitrofurantoin can be life threatening and nitrofurantoin should be stopped immediately on occurance of symptoms. Impaired pulmonary function may remain even after cessation of therapy. Deaths as a result of cardiopulmonary collapse and of alveolar hemorrhage have been reported. Hematological disorders - and of special significance, hemolytic anaemia associated with use in patients with G-6-PD deficiency have been reported in association with nitrofurantoin use. Additional hematologic effects include leukopenia, granulocytopenia, agranulocytosis, thrombocytopenia, and aplastic anemia. Dermatologic reactions include Stevens Johnson syndrome and other rashes. ANIMAL STUDIES: Carcinogenicity: Nitrofurantoin does not appear to be carcinogenic. There is increased ovarian cancer in mice with chronic, high dose administration. It was found to be carcinogenic in B6C3F female mice and in F344/N male rats. Teratogenicity: There is no evidence to link nitrofurantoin to birth defects in animals.
Nitrofurantoin is currently one of the most common causes of drug induced liver injury. Liver injury from nitrofurantoin can cause either an acute or chronic hepatitis-like syndrome. The acute form is typically associated with a 1 or 2 week course of treatment with nitrofurantoin and is rare (~0.3 cases per 100,000 prescriptions). Acute liver injury typically presents within a few weeks of starting nitrofurantoin and can arise up to a few weeks after stopping a defined course of treatment. The pattern of liver injury is usually hepatocellular with or without jaundice, and typically is accompanied by symptoms of fever and rash. The acute injury due to nitrofurantoin usually resolves rapidly once the medication is stopped, but severe and fatal instances have been reported. In some instances, autoimmune features are present, but these are more common with the chronic presentation of nitrofurantoin hepatotoxicity. The course and outcome of acute nitrofurantoin hepatotoxicity is variable, severe forms with acute liver failure can occur, and nitrofurantoin is regularly listed as one of the major causes of acute liver failure due to medications.
The chronic form of nitrofurantoin hepatotoxicity is more common than the acute form and typically presents months to years after initiation of long term prophylactic therapy. The estimated incidence of liver injury from nitrofurantoin is approximately 1 per 1500 persons exposed. The presentation is usually insidious and marked initially by fatigue and weakness followed by dark urine and jaundice. The clinical pattern and laboratory features can mimic autoimmune hepatitis with marked elevations in serum ALT levels, increases in gamma globulin levels, and the presence of antinuclear and anti-smooth muscle antibodies. In some instances, the onset is abrupt and resembles acute hepatitis. However, immunoallergic features of fever and rash are less common than with the acute form of nitrofurantoin hepatotoxicity. Liver histology typically demonstrates features of chronic hepatitis with inflammation, interface hepatitis, focal or centrilobular bridging necrosis and variable degrees of fibrosis. Cirrhosis as a result of nitrofurantoin hepatotoxicity has been reported and, if not recognized as due to the medication, can progress to end stage liver disease. There is a female preponderance and the risk of injury appears to increase with age particularly the chronic forms.
Likelihood score: A (well known cause of clinically apparent liver injury).
Nitrofurantoin reaches a Cmax of 0.875-0.963mg/L with an AUC of 2.21-2.42mg\*h/L. It is 38.8-44.3% bioavailable. Taking nitrofurantoin with food increases the absorption and duration of therapeutic concentrations in the urine.
来源:DrugBank
吸收、分配和排泄
消除途径
27-50%的口服剂量以未改变的硝基呋喃妥因形式通过尿液排出。总剂量的90%通过尿液消除。
27-50% of an oral dose is excreted in the urine as unchanged nitrofurantoin. 90% of the total dose is eliminated in the urine.
来源:DrugBank
吸收、分配和排泄
分布容积
关于药物在人体内的分布体积的数据很少，但在狗身上报告的分布体积为0.46升/千克。
Data regarding the volume of distribution in humans is scarce but it has been reported as 0.46L/kg in dogs.
.../IT/ IS RAPIDLY & COMPLETELY ABSORBED FROM GI TRACT. ... PLASMA HALF-LIFE IS 0.3 TO 1 HR; ABOUT 40% IS EXCRETED UNCHANGED INTO URINE. AVG DOSE OF NITROFURANTOIN YIELDS URINE CONCN OF APPROX 200 UG/ML. ... RATE OF EXCRETION IS LINEARLY RELATED TO CREATININE CLEARANCE...
Microsomal oxidative stress induced by NADPH is inhibited by nitrofurantoin redox biotranformation
摘要：
Nitrofurantoin is used in the antibacterial therapy of the urinary tract. This therapy is associated with various adverse effects whose mechanisms remain unclear. Diverse studies show that the nitro reductive metabolism of nitrofurantoin leads to ROS generation. This reaction can be catalyzed by several reductases, including the cytochrome P450 (CYP450) reductase. Oxidative stress arising from this nitro reductive metabolism has been proposed as the mechanism underlying the adverse effects associated with nitrofurantoin. There is, however, an apparent paradox between these findings and the ability of nitrofurantoin to inhibit lipid peroxidation provoked by NADPH in rat liver microsomes. This work was aimed to show the potential contribution of different enzymatic systems to the metabolism of this drug in rat liver microsomes. Our results show that microsomal lipid peroxidation promoted by NADPH is inhibited by nitrofurantoin in a concentration-dependent manner. This suggests that the consumption of NADPH in microsomes can be competitively promoted by lipid peroxidation and nitrofurantoin metabolism. The incubation of microsomes with NADPH and nitrofurantoin generated 1-aminohidantoin. In addition, the biotransformation of a classical substrate of CYP450 oxidative system was competitively inhibited by nitrofurantoin. These results suggest that nitrofurantoin is metabolized through CYP450 system. Data are discussed in terms of the in vitro redox metabolism of nitrofurantoin.
Eflornithine Prodrugs, Conjugates and Salts, and Methods of Use Thereof
申请人：Xu Feng
公开号：US20100120727A1
公开（公告）日：2010-05-13
In one aspect, the present invention provides a composition of a covalent conjugate of an eflornithine analog with an anti-inflammatory drug. In another aspect, the present invention provides a composition of an eflornithine prodrug. In another aspect, the present invention provides a composition of an eflornithine or its derivatives aspirin salt. In another aspect, the present invention provides methods for treating or preventing cancer using the conjugates or salts of eflornithine analogs or eflornithine prodrugs.
[EN] METALLOENZYME INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS DE MÉTALLOENZYMES
申请人：VPS 3 INC
公开号：WO2018165520A1
公开（公告）日：2018-09-13
Provided are compounds having HDAC6 modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by HDAC6.
提供具有HDAC6调节活性的化合物，以及通过HDAC6介导的治疗疾病、疾病或症状的方法。
[EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2017046658A1
公开（公告）日：2017-03-23
Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.
[EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020257998A1
公开（公告）日：2020-12-30
Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.
[EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020006722A1
公开（公告）日：2020-01-09
A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
