Hydrocortisone is metabolised to 6-beta hydrocortisol via CYP3A, 5-beta tetrahydrocortisol via 3-oxo-5-beta-steroid 4-dehydrogenase, 5-alpha tetrahydrocortisol via 3-oxo-5-alpha-steroid 4-dehydrogenase 2, cortisone via Corticosteroid 11-beta-dehydrogenase isozyme 1 and Corticosteroid 11-beta-dehydrogenase isozyme 2, and glucuronide products. Cortisone is further metabolized to tetrahydrocortisone and dihydrocortisol.
A study was made of the absorption of exogenous hydrocortisone and formation of its metabolites in isolated liver of intact and exposed rats in conditions of recirculating perfusion. It was shown that the absorption of the hormone by the liver of irradiated rats was greatly lowered but the content of most metabolites found in the perfused medium of irradiated liver increased as compared to the control. It is suggested that irradiation inhibits subsequent transformations of the hydrocortisone metabolism products.
Subcellular distribution of (3)H-hydrocortisone and its metabolites in the liver and kidney of intact and alloxan diabetic rats was investigated. Ten minutes after the administration of this hormone several metabolites (mostly tetrahydrocortisol) and the native hormone were found in liver cytosol, microsomes, mitochondria and nuclei, the relative content of individual compounds in various subcellular fractions being different. In liver mitochondria, microsomes and nuclei of alloxan diabetic rats the concentration of tetrahydrocortisol was decreased, while that of native hormone was increased as compared to normal animals. It was suggested that such changes found in diabetic animals may be one of the causes of increased sensitivity of transcription and translation processes to glucocorticoids. In kidney cytosol and microsomes of intact rats cortisone and tetrahydrocortisol were found. In diabetic animals, however, the concentration of tetrahydrocortisol increased, while that of cortisone was undetectable.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 用于研究药物诱导肝损伤的FDA批准药物标签，药物发现今天，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按在人类中发展药物诱导肝损伤风险排名的最大参考药物清单。药物发现今天 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
◉ Summary of Use during Lactation:Hydrocortisone (cortisol) is a normal component of breastmilk, but it has not been studied in milk after exogenous administration in pharmacologic amounts. Although it is unlikely that dangerous amounts of hydrocortisone would reach the infant, a better studied alternate corticosteroid might be preferred. Maternal use of hydrocortisone as an enema would not be expected to cause any adverse effects in breastfed infants. Local maternal injections, such as for tendinitis, would not be expected to cause any adverse effects in breastfed infants, but might occasionally cause temporary loss of milk supply. See also Hydrocortisone, Topical.
Cortisol in breastmilk might have a role in intestinal maturation, the intestinal microbiome, growth, body composition or neurodevelopment, but adequate studies are lacking. Concentrations follow a diurnal rhythm, with the highest concentrations in the morning at about 7:00 am and the lowest concentrations in the late afternoon and evening. Maternal stress can increase breastmilk cortisol levels. Cortisol in milk may protect against later infant obesity, especially in girls; however, in another study, milk glucocorticoid levels were positively associated with percent fat mass, adiposity and head circumference at 1 year of age.
Cortisol concentrations in breastmilk are not affected by storage for 36 hours at room temperature, during multiple freeze-thaw cycles, and very little by Holder pasteurization (62.5 degrees C for 30 minutes).
◉ Effects in Breastfed Infants:None reported with any systemic corticosteroid.
◉ Effects on Lactation and Breastmilk:Published information on the effects of hydrocortisone on serum prolactin or on lactation in nursing mothers was not found as of the revision date. However, medium to large doses of depot corticosteroids injected into joints have been reported to cause temporary reduction of lactation.
A study of 46 women who delivered an infant before 34 weeks of gestation found that a course of another corticosteroid (betamethasone, 2 intramuscular injections of 11.4 mg of betamethasone 24 hours apart) given between 3 and 9 days before delivery resulted in delayed lactogenesis II and lower average milk volumes during the 10 days after delivery. Milk volume was not affected if the infant was delivered less than 3 days or more than 10 days after the mother received the corticosteroid. An equivalent dosage regimen of hydrocortisone might have the same effect.
A study of 87 pregnant women found that betamethasone given as above during pregnancy caused a premature stimulation of lactose secretion during pregnancy. Although the increase was statistically significant, the clinical importance appears to be minimal. An equivalent dosage regimen of hydrocortisone might have the same effect.
Oral hydrocortisone at a dose of 0.2-0.3mg/kg/day reached a mean Cmax of 32.69nmol/L with a mean AUC of 90.63h\*nmol/L A 0.4-0.6mg/kg/day dose reached a mean Cmax of 70.81nmol/L with a mean AUC of 199.11h\*nmol/L. However, the pharmacokinetics of hydrocortisone can vary by 10 times from patient to patient. Topical hydrocortisone cream is 4-19% bioavailable[8546995] with a Tmax of 24h. Hydrocortisone retention enemas are have a bioavailability of 0.810 for slow absorbers and 0.502 in rapid absorbers. Slow absorbers take up hydrocortisone at a rate of 0.361±0.255/h while fast absorbers take up hydrocortisone at a rate of 1.05±0.255/h. A 20mg IV dose of hydrocortisone has an AUC of 1163±277ng\*h/mL.
来源:DrugBank
吸收、分配和排泄
消除途径
皮质类固醇主要通过尿液排出。然而，关于确切比例的数据并不容易获得。
Corticosteroids are eliminated predominantly in the urine. However, data regarding the exact proportion is not readily available.
来源:DrugBank
吸收、分配和排泄
分布容积
总氢化可的松的分布容积为39.82升，而游离部分的分布容积为474.38升。
Total hydrocortisone has a volume of distribution of 39.82L, while the free fraction has a volume of distribution of 474.38L.
Total hydrocortisone by the oral route has a mean clearance of 12.85L/h, while the free fraction has a mean clearance of 235.78L/h. A 20mg IV dose of hydrocortisone has a clearance of 18.2±4.2L/h.
Following percutaneous penetration of a topical corticosteroid, the drug that is systemically absorbed probably follows the metabolic pathways of systemically administered corticosteroids. Corticosteroids usually are metabolized in the liver and excreted by the kidneys. Some topical corticosteroids and their metabolites are excreted in bile. /Topical corticosteroids/
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
申请人：Vertex Pharmaceuticals Incorporated
公开号：US20150231142A1
公开（公告）日：2015-08-20
The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
[EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
申请人：TAKEDA PHARMACEUTICAL
公开号：WO2010144486A1
公开（公告）日：2010-12-16
Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.
[EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
申请人：GALAPAGOS NV
公开号：WO2017012647A1
公开（公告）日：2017-01-26
The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.
[EN] ARYL ETHER-BASE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE KINASES DE TYPE ARYLÉTHER-BASE
申请人：BRISTOL MYERS SQUIBB CO
公开号：WO2015038112A1
公开（公告）日：2015-03-19
The present disclosure is generally directed to compounds which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAK1.
