Dutasteride undergoes extensive hepatic metabolism mediated by CYP3A4 and CYP3A5. 4′-hydroxydutasteride, 6-hydroxydutasteride, 6,4′-dihydroxydutasteride, 1,2-dihydrodutasteride, and 15-hydroxydutasteride metabolites are formed. 2 minor metabolites - 6,4′-dihydroxydutasteride and 15-hydroxydutasteride - can also be detected. According to _in vitro_ studies, 4′-hydroxydutasteride and 1,2-dihydrodutasteride mediated inhibitory actions against both isoforms of 5α-reductase but with lower potency when compared to the parent drug. The activity of 6β-hydroxydutasteride is comparable to that of dutasteride.
Dutasteride has been associated with a low rate of serum aminotransferase elevations that, in controlled trials, was no higher than with placebo therapy. These elevations were transient and rarely required dose modification. There have been no published reports of clinically apparent liver injury due to dutasteride therapy.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，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：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》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
Following oral administration of a single dose of 0.5 mg dutasteride, the peak serum concentrations were reached within 2 to 3 hours. Following daily oral administration of 0.5 mg dutasteride, the steady-state concentration of 40 ng/mL is expected to be achieved at 6 months following initial administration. In healthy subjects, the absolute bioavailability was 60%, ranging from 40% to 94%. While food intake reduced the maximum serum concentrations by 10 to 15%, food intake is reported to have a negligible effect on the bioavailability of the drug.
Dutasteride and its metabolites mainly undergo fecal excretion. About 1-15% of the dose is excreted as the unchanged parent compound, while 2-90% of the total dose is excreted in the form of dutasteride-related metabolites in the feces. Trace amounts of unchanged dutasteride, with less than 1%, can also be detected in the urine. Therefore, on average, the dose unaccounted for approximated 55%, with a range between 5% and 97%.
Dutasteride displays a large volume of distribution ranging from 300 to 500 L. Following daily oral administration of 0.5 mg dutasteride healthy subjects for 12 months, the semen dutasteride concentrations averaged 3.4 ng/mL (range: 0.4 to 14 ng/mL) with 11.5% of serum dutasteride concentrations being partitioned into semen.
In a study of healthy volunteers receiving single oral doses of dutasteride ranging from 0.01 to 40 mg, dutasteride displayed a low linear clearance of 0.58 L/h. The estimated inter-individual variability for the linear clearance was high.
[EN] PROCESS FOR THE SYNTHESIS OF (5a,17ß)-N-[(2,5-BIS(TRIFLUOROMETHYL)-PHENYL]-3-OXO-4-AZA-5-ANDROST-1-ENE-17-CARBOXAMIDE [FR] PROCÉDÉ DE SYNTHÈSE DU (5?,17?)-N-[(2,5-BIS(TRIFLUOROMÉTHYL)-PHÉNYL]-3-OXO-4-AZA-5-ANDROST-1-ÈNE-17-CARBOXAMIDE
[EN] PYRIMIDINE JAK INHIBITORS FOR THE TREATMENT OF SKIN DISEASES<br/>[FR] INHIBITEURS DE JAK À BASE DE PYRIMIDINE POUR LE TRAITEMENT DE MALADIES DE LA PEAU
申请人：THERAVANCE BIOPHARMA R&D IP LLC
公开号：WO2020219640A1
公开（公告）日：2020-10-29
The invention provides compounds of formula (I): or pharmaceutically-acceptable salts thereof, that are inhibitors of Janus kinases. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat inflammatory and autoimmune skin diseases.
Benzene Sulfonamide Thiazole and Oxazole Compounds
申请人：Adams Jerry Leroy
公开号：US20090298815A1
公开（公告）日：2009-12-03
The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
[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.
[EN] AMIDOIMIDAZOPYRIDAZINES AS MKNK-1 KINASE INHIBITORS<br/>[FR] AMIDOIMIDAZOPYRIDAZINES À TITRE D'INHIBITEURS DE KINASES MKNK-1
申请人：BAYER PHARMA AG
公开号：WO2014118135A1
公开（公告）日：2014-08-07
The present invention relates to amido-substituted imidazopyridazine compounds of general formula (I) : in which A, R1, R2, R3, R4 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
