Budesonide is metabolized in the liver by the cytochrome P-450 (CYP) isoenzyme 3A4; the 2 main metabolites have less than 1% of affinity for glucocorticoid receptors than the parent compound. Budesonide is excreted in urine and feces as metabolites.
Asthma is one of the most prevalent diseases in the world, for which the mainstay treatment has been inhaled glucocorticoids (GCs). Despite the widespread use of these drugs, approximately 30% of asthma sufferers exhibit some degree of steroid insensitivity or are refractory to inhaled GCs. One hypothesis to explain this phenomenon is interpatient variability in the clearance of these compounds. The objective of this research is to determine how metabolism of GCs by the CYP3A family of enzymes could affect their effectiveness in asthmatic patients. In this work, the metabolism of four frequently prescribed inhaled GCs, triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate, by the CYP3A family of enzymes was studied to identify differences in their rates of clearance and to identify their metabolites. Both interenzyme and interdrug variability in rates of metabolism and metabolic fate were observed. CYP3A4 was the most efficient metabolic catalyst for all the compounds, and CYP3A7 had the slowest rates. CYP3A5, which is particularly relevant to GC metabolism in the lungs, was also shown to efficiently metabolize triamcinolone acetonide, budesonide, and fluticasone propionate. In contrast, flunisolide was only metabolized via CYP3A4, with no significant turnover by CYP3A5 or CYP3A7. Common metabolites included 6 Beta-hydroxylation and Delta (6)-dehydrogenation for triamcinolone acetonide, budesonide, and flunisolide. The structure of Delta (6)-flunisolide was unambiguously established by NMR analysis. Metabolism also occurred on the D-ring substituents, including the 21-carboxy metabolites for triamcinolone acetonide and flunisolide. The novel metabolite 21-nortriamcinolone acetonide was also identified by liquid chromatography-mass spectrometry and NMR analysis.
IDENTIFICATION AND USE: Budesonide (trade names: Rhinocort, MMX) is a prescription medication approved for the treatment of allergic rhinitis (Rhinocort nasal spray) and mild to moderate Crohn's disease (MMX, enteric coated capsules). HUMAN EXPOSURE AND TOXICITY: Patch tests have indicated that budesonide can produce delayed allergic reactions, and atopic dermatitis. In cases of inhalational exposure, periorificial dermatitis has been reported. In cases of oral administration, Candida albicans esophagitis, dysphagia, elevated blood pressure, lower extremity edema, and weight gain have been reported, although some of these adverse events may have been the result of a drug interaction with voriconazole. Epidemiological studies have found an increased risk of pneumonia, cardiac dysrhythmias, cataracts, and fractures associated with inhaled budesonide use. Additional epidemiological studies have found that budesonide inhalation during pregnancy may be a risk factor for offspring endocrine and metabolic disturbances. Low birth weight has also been reported. In children taking budesonide for persistent asthma, slower linear growth, slow weight gain, and slow skeletal maturation have also been observed. Localized Candidal infections of the nose and pharynx has been reported during intranasal budesonide therapy. Patients may be at an increased risk for certain infections, such as Varicella (chickenpox). In children and adolescents, administration of budesonide may cause growth suppression. It may also cause acute or delayed hypersensitivity reactions. Hypoadrenalism may occur in infants of mothers receiving corticosteroid therapy during pregnancy. ANIMAL STUDIES: In carcinogenicity studies, hepatocellular tumors and gliomas have been observed in rats that received oral budesonide. In female rats that received budesonide subcutaneously, a decrease in prenatal viability and viability of pups during pregnancy and lactation was observed. Pyloric hyalinization was detected in mice that received budesonide orally.
Long term therapy with budesonide has not been linked to elevations in serum enzyme levels, and in clinical trials rates of ALT elevations were similar with budesonide as with placebo treatment. In controlled trials, there were no reported cases of clinically apparent liver injury associated with its use. Unlike conventional systemically administered corticosteroids, budesonide has not been linked to episodes of reactivation of hepatitis B. Budesonide has been used in severe autoimmune liver diseases without evidence that it causes worsening of liver injury. Because it can improve serum aminotransferase elevations in patients with autoimmune hepatitis, its withdrawal may be followed by rebound elevations as also occurs with conventional corticosteroid therapy. In addition, there has been a single case report of acute serum aminotransferase elevations during budesonide therapy that resolved when the drug was stopped, but documentation was limited and the patient was on multiple other potentially hepatotoxic drugs.
◉ Summary of Use during Lactation:The amounts of inhaled budesonide excreted into breastmilk are minute and infant exposure is negligible. When taken by mouth, budesonide is only about 9% bioavailable; bioavailability in the infant is likely to be similarly low for any budesonide that enters the breastmilk. Expert opinion considers inhaled, nasal and oral corticosteroids acceptable to use during breastfeeding.
◉ Effects in Breastfed Infants:None reported with any corticosteroid.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
Steroid psychosis has been well described with oral glucocorticoids, however, our search of the literature did not identify an association between delirium and the combination of inhaled glucocorticoids and long-acting beta-agonists. We describe the occurrence of delirium with the combination of an inhaled glucocorticoid and bronchodilator. An elderly male described confusion and hallucinations within 1 week after initiation of budesonide/formoterol for chronic obstructive pulmonary disease. The combination inhaler was discontinued with resolution of symptoms. Several weeks later, the patient was hospitalized and restarted on the combination inhaler. The patient was alert and oriented on admission, however, confusion and hallucinations progressed throughout his hospital stay. The combination inhaler was discontinued and his confusion and hallucinations resolved by discharge. The temporal relationship of these events and a probable Naranjo association allows for reasonable assumption that the use of the budesonide/formoterol combination inhaler caused or contributed to the occurrences of delirium in this elderly patient. The onset of delirium was likely due to the systemic absorption of the glucocorticoid from lung deposition, complicated in an individual with several predisposing risk factors for delirium. Health care providers should be aware of this potential adverse drug reaction when prescribing inhaled medications to older patients at risk for delirium.
A 48-year-old woman with HIV infection developed Cushingoid features while she was taking ritonavir-boosted darunavir. Cushing's syndrome was confirmed due to the drug interaction between ritonavir and budesonide. Diagnosis of iatrogenic Cushing's syndrome in HIV-positive patients who are on ritonavir-boosted protease inhibitors (PIs) presents a clinical challenge due to similar clinical features of lipohypertrophy related to ritonavir-boosted PIs. Although this complication has been widely described with the use of inhaled fluticasone, the interaction with inhaled budesonide at therapeutic dose is not widely recognized.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
/MILK/ 尚不清楚布地奈德是否分布到牛奶中。
/MILK/ Not known whether budesonide is distributed in milk.
When budesonide is administered intranasally, approximately 34% of a dose reaches systemic circulation. Mean peak plasma budesonide concentrations are achieved in about 0.7 hours.
Inhaled corticosteroids (ICS) are mainstay treatment of asthma and chronic obstructive pulmonary disease. However, highly lipophilic ICS accumulate in systemic tissues, which may lead to adverse systemic effects. The accumulation of a new, highly lipophilic ICS, ciclesonide and its active metabolite (des-CIC) has not yet been reported. Here, we have compared tissue accumulation of des-CIC and an ICS of a moderate lipophilicity, budesonide (BUD), after 14 days of once-daily treatment in mice. Single, three or 14 daily doses of [(3) H]-des-CIC or [(3) H]-BUD were administered subcutaneously to male CD1 albino mice, which were killed at 4 hrs, 24 hrs or 5 days after the last dose. Distribution of tissue concentration of radioactivity was studied by quantitative whole-body autoradiography. Pattern of radioactivity distribution across most tissues was similar for both corticosteroids after a single as well as after repeated dosing. However, tissue concentration of radioactivity differed between des-CIC and BUD. After a single dose, concentrations of radioactivity for both corticosteroids were low for most tissues but increased over 14 days of daily dosing. The tissue radioactivity of des-CIC at 24 hrs and 5 days after the 14th dose was 2-3 times higher than that of BUD in majority of tissues. Tissue accumulation, assessed as concentration of tissue radioactivity 5 days after the 14th versus 3rd dose, showed an average ratio of 5.2 for des-CIC and 2.7 for BUD (p < 0.0001). In conclusion, des-CIC accumulated significantly more than BUD. Systemic accumulation may lead to increased risk of adverse systemic side effects during long-term therapy.
Azo-reductase activated budesodine prodrugs for colon targeting
摘要：
Budesodine is a synthetic glurocorticoid that undergoes substantial first pass metabolism, limiting systemic exposure. Its use in treatment of inflammatory bowel disease would benefit from a targeting strategy that could lead to a local topical effect, improving safety and increasing anti-inflammatory efficacy. A two-step prodrug strategy involving azoreduction/cyclization that we developed previously for prednisolone is here applied with some variations to budesonide. The budesodine prodrugs were tested using an in vitro azoreductase assay simulating human colonic microflora. The kinetics of amino steroid ester cyclization and its pH dependence was also evaluated. The stability of the prodrugs systems in simulated human duodenal and gastric fluid was evaluated to determine the likelihood of intact intestinal transit. The propionic acid derived prodrug 3 undergoes rapid activation by Clostridium perfingens and its putative reduction product cyclizes with acceptable rapidity when synthesized independently. These properties of 3 suggest that it has potential in management of ulcerative colitis. (c) 2012 Elsevier Ltd. All rights reserved.
[EN] HETEROCYCLIC AMIDES USEFUL AS PROTEIN MODULATORS<br/>[FR] AMIDES HÉTÉROCYCLIQUES UTILES EN TANT QUE MODULATEURS DE PROTÉINE
申请人：GLAXOSMITHKLINE IP DEV LTD
公开号：WO2017175147A1
公开（公告）日：2017-10-12
Disclosed are compounds having the formula (I-N), wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, and R17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof.
[EN] MODULATORS OF STIMULATOR OF INTERFERON GENES (STING) USEFUL IN TREATING HIV<br/>[FR] MODULATEURS DE STIMULATEUR DES GÈNES (STING) D'INTERFÉRON UTILES DANS LE TRAITEMENT DU VIH
申请人：GLAXOSMITHKLINE IP DEV LTD
公开号：WO2019069269A1
公开（公告）日：2019-04-11
Disclosed are compounds having the formula: (I-N) wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, and R17, are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof, along with combinations thereof, all of which are useful in HIV therapies.
The present invention provides a compound of Formula (I) or the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are ERK2 inhibitors. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and a pharmaceutically acceptable carrier. The invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula (I) and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.
[EN] NITROGEN RING CONTAINING COMPOUNDS FOR TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] COMPOSÉS CONTENANT UN CYCLE AZOTÉ POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
申请人：WEINGARTEN M DAVID
公开号：WO2012135669A1
公开（公告）日：2012-10-04
The invention provides compounds, pharmaceutical compositions and methods of treatment of inflammatory disorders including a compound of Formula I, or its pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative or prodrug wherein R1, R2, R3, R4, X, Y, W, Z and Q are as defined herein.
[EN] TRICYCLIC INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE<br/>[FR] INHIBITEURS TRICYCLIQUES DE POLY(ADP-RIBOSE)POLYMÉRASE
申请人：NEWGEN THERAPEUTICS INC
公开号：WO2012166983A1
公开（公告）日：2012-12-06
The invention provides for compositions comprising phosphorous containing tricyclic compounds, including phthalazin-l(2H)-one derivatives. The compounds are potent inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), particularly PARP-1 and potentially PARP-2. The also show good cellular activity in inhibiting poly(ADP- ribose) oligomer formation. The compounds may be useful as mono-therapy or in combination with other therapeutic agents in the treatment conditions where PARP is implicated, such as cancer, inflammatory diseases and ischemic conditions. Thus, also provided are methods for the treatment of a condition where PARP is implicated comprising administering to an effective amount of a compound of the invention to an individual in need thereof.
