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.
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.
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.
To present two cases of iatrogenic Cushing syndrome caused by the interaction of budesonide, an inhaled glucocorticoid, with ritonavir and itraconazole, we present the clinical and biochemical data of two patients in whom diagnosis of Cushing syndrome was caused by this interaction. A 71-year-old man was treated with inhaled budesonide for a chronic obstructive pulmonary disease and itraconazole for a pulmonary aspergillosis. The patient rapidly developed a typical Cushing syndrome complicated by bilateral avascular necrosis of the femoral heads. Serum 8:00 AM cortisol concentrations were suppressed at 0.76 and 0.83 ug/dL on two occasions. The patient died 4 days later of a massive myocardial infarction. The second case is a 46-year-old woman who was treated for several years with inhaled budesonide for asthma. She was put on ritonavir, a retroviral protease inhibitor, for the treatment of human immunodeficiency virus (HIV). In the following months, she developed typical signs of Cushing syndrome. Her morning serum cortisol concentration was 1.92 ug/dL. A cosyntropin stimulation test showed values of serum cortisol of <1.10, 2.65, and 5.36 ug/dL at 0, 30, and 60 minutes, respectively, confirming an adrenal insufficiency. Because the patient was unable to stop budesonide, she was advised to reduce the frequency of its administration and eventually taper the dose until cessation. Clinicians should be aware of the potential occurrence of iatrogenic Cushing syndrome and secondary adrenal insufficiency due to the association of inhaled corticosteroids with itraconazole or ritonavir.
Oral budesonide is commonly used for the management of Crohn's disease given its high affinity for glucocorticoid receptors and low systemic activity due to extensive first-pass metabolism through hepatic cytochrome P450 (CYP) 3A4. Voriconazole, a second-generation triazole antifungal agent, is both a substrate and potent inhibitor of CYP isoenzymes, specifically CYP2C19, CYP2C9, and CYP3A4; thus, the potential for drug-drug interactions with voriconazole is high. To our knowledge, drug-drug interactions between voriconazole and corticosteroids have not been specifically reported in the literature. We describe a 48-year-old woman who was receiving oral budesonide 9 mg/day for the management of Crohn's disease and was diagnosed with fluconazole-resistant Candida albicans esophagitis; oral voriconazole 200 mg every 12 hours for 3 weeks was prescribed for treatment. Because the patient experienced recurrent symptoms of dysphagia, a second 3-week course of voriconazole therapy was taken. Seven weeks after originally being prescribed voriconazole, she came to her primary care clinic with elevated blood pressure, lower extremity edema, and weight gain; she was prescribed a diuretic and evaluated for renal dysfunction. At a follow-up visit 6 weeks later with her specialty clinic, the patient's blood pressure was elevated, and her physical examination was notable for moon facies, posterior cervical fat pad prominence, and lower extremity pitting edema. Iatrogenic Cushing syndrome due to a drug-drug interaction between voriconazole and budesonide was suspected, and voriconazole was discontinued. Budesonide was continued as previously prescribed for her Crohn's disease. On reevaluation 2 months later, the patient's Cushingoid features had markedly regressed. To our knowledge, this is the first published case report of iatrogenic Cushing syndrome due to a probable interaction between voriconazole and oral budesonide. In patients presenting with Cushingoid features who have received these drugs concomitantly, clinicians should consider the potential drug interaction between these agents, and the risks and benefits of continued therapy must be considered.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
/MILK/ 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.
[EN] ANTI-MSR1 ANTIBODIES AND METHODS OF USE THEREOF<br/>[FR] ANTICORPS ANTI-MSR1 ET LEURS PROCÉDÉS D'UTILISATION
申请人：REGENERON PHARMA
公开号：WO2019217591A1
公开（公告）日：2019-11-14
Provided herein are antibodies and antigen-binding fragments that bind MSR1 and methods of use thereof. According to certain embodiments, the antibodies bind human MSR1 with high affinity. In certain embodiments, the antibodies bind MSR1 without blocking, or blocking less than 90%, of modified LDL binding to MSR1. In some embodiments, the antibodies bind cell surface expressed-MSR1 and are internalized. The antibodies of the invention may be fully human antibodies. The invention includes anti-MSR1 antibodies, or antigen-binding fragments thereof, conjugated to drugs or therapeutic compounds.
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