Hydroxychloroquine is N-dealkylated by CYP3A4 to the active metabolite desethylhydroxychloroquine, as well as the inactive metabolites desethylchloroquine and bidesethylchloroquine. Desethylhydroxychloroquine is the major metabolite.
Partially hepatic, to active de-ethylated metabolites.
Half Life: Terminal elimination half-life In blood is approximately 50 days. In plasma it is approximately 32 days.
Although the exact mechanism of action is unknown, it may be based on ability of hydroxychloroquine to bind to and alter DNA. Hydroxychloroquine has also has been found to be taken up into the acidic food vacuoles of the parasite in the erythrocyte. This increases the pH of the acid vesicles, interfering with vesicle functions and possibly inhibiting phospholipid metabolism. In suppressive treatment, hydroxychloroquine inhibits the erythrocytic stage of development of plasmodia. In acute attacks of malaria, it interrupts erythrocytic schizogony of the parasite. Its ability to concentrate in parasitized erythrocytes may account for their selective toxicity against the erythrocytic stages of plasmodial infection. As an antirheumatic, hydroxychloroquine is thought to act as a mild immunosuppressant, inhibiting the production of rheumatoid factor and acute phase reactants. It also accumulates in white blood cells, stabilizing lysosomal membranes and inhibiting the activity of many enzymes, including collagenase and the proteases that cause cartilage breakdown.
Hydroxychloroquine has not been associated with significant serum enzyme elevations during therapy of rheumatologic diseases. Furthermore, clinically apparent liver injury from hydroxychloroquine is rare. A single case series (two cases) of acute liver failure attributed to hydroxychloroquine was published twenty years ago, but case reports of clinically apparent liver injury have not appeared subsequently. Thus, acute liver injury with jaundice due to hydroxychloroquine must be very rare, if it occurs at all. In clinical trials of hydroxychloroquine for COVID-19 prevention and treatment, there were no reports of hepatotoxicity and rates of serum enzyme elevations during hydroxychloroquine treatment were low and similar to those in patients receiving placebo or comparator agents.
An exception to this is the use of hydroxychloroquine in patients with porphyria cutanea tarda. When used in relatively high doses, hydroxychloroquine can trigger an acute hepatic injury with sudden onset of fever and marked serum enzyme elevations with increased excretion of porphyrins. This reaction appears to be caused by the sudden mobilization of porphyrins and is often followed by an improvement in porphyric symptoms. The reaction is uncommon if therapy is started with lower doses of hydroxychloroquine and is less severe than similar reactions that occur with chloroquine. Indeed, chronic low doses of hydroxychloroquine (100 to 200 mg twice weekly) have been used to alleviate symptoms in patients with prophyria cutanea tarda who are resistant or intolerant of phlebotomy, the usual therapy of this condition.
Likelihood score: C (probable rare cause of idiosyncratic, clinically apparent liver injury, but capable of causing acute hepatoxicity with moderately high doses in patients with porphyria).
Hydroxychloroquine is 67-74% bioavailable. Bioavailability of the R and S enantiomers were not significantly different. Following a 200mg oral dose, hydroxychloroquine reached a Cmax of 129.6ng/mL with a Tmax of 3.26h in the blood and a Cmax of 50.3ng/mL with a Tmax of 3.74h in the plasma. Following 155mg and 310mg intravenous doses, Cmax in the blood ranged from 1161-2436ng/mL with an average of 1918ng/mL.
40-50% of hydroxychloroquine is excreted renally, while only 16-21% of a dose is excreted in the urine as unchanged drug. 5% of a dose is sloughed off in skin and 24-25% is eliminated through the feces.
来源:DrugBank
吸收、分配和排泄
分布容积
羟氯喹的血液分布体积为5522升，血浆分布体积为44,257升。
Hydroxychloroquine has a volume of distribution of 5522L from blood and 44,257L from plasma.
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.
SULFONAMIDE, SULFAMATE, AND SULFAMOTHIOATE DERIVATIVES
申请人：Wang Zhong
公开号：US20120077814A1
公开（公告）日：2012-03-29
The disclosure provides biologically active compounds of formula (I):
and pharmaceutically acceptable salts thereof, compositions containing these compounds, and methods of using these compounds in a variety applications, such as treatment of diseases or disorders associated with E1 type activating enzymes, and with Nedd8 activating enzyme (NAE) in particular.
[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] CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF<br/>[FR] MODULATEURS DE CALPAÏNE ET LEURS UTILISATIONS THÉRAPEUTIQUES
申请人：BLADE THERAPEUTICS INC
公开号：WO2019190885A1
公开（公告）日：2019-10-03
Small molecule calpain modulator compounds, including their pharmaceutically acceptable salts, can be included in pharmaceutical compositions. The compounds can be useful in inhibiting calpain, or competitive binding with calpastatin, by contacting them with CAPN1, CAPN2, and/or CAPN9 enzymes residing inside a subject. The compounds and composition can also be administered to a subject in order to treat a fibrotic disease or a secondary disease state or condition of a fibrotic disease.
