Gemifloxacin is metabolized to a limited extent by the liver. All metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin.
Gemifloxacin is metabolized to a limited extent by the liver. The unchanged compound is the predominant drug-related component detected in plasma (approximately 65%) up to 4 hours after dosing. All metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin. Cytochrome P450 enzymes do not play an important role in gemifloxacin metabolism, and the metabolic activity of these enzymes is not significantly inhibited by gemifloxacin.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
肝毒性
吉米氟沙星（jem" i flox' a sin），与其他氟喹诺酮类药物一样，在治疗期间与低比率的血清酶升高（1%至7%）有关，尽管这个比率可能略高于安慰剂或比较药物。这些异常通常是轻微的，无症状且短暂的，即使在继续治疗的情况下也会解决。由于吉米氟沙星导致的肝毒性的报告病例太少，无法提供其临床特征和病程的可靠描述。然而，氟喹诺酮类药物的肝损伤似乎是一种类药物效应，吉米氟沙星的损伤似乎也具有这些特征。它是导致肝损伤的较不常见原因，不如环丙沙星、左氧氟沙星或莫西沙星常见，但已有病例报告。一般来说，氟喹诺酮类药物的肝毒性特点是发病时间短（几天到3周）；常突然出现明显的恶心、疲劳、腹痛和黄疸。血清酶升高的模式可以是肝细胞型或胆汁淤积型，发病时间较短的病例通常更倾向于肝细胞型，表现为ALT水平显著升高，偶尔伴有凝血酶原时间的快速恶化和肝功能衰竭的迹象。疾病发作可能在停药后几天内发生。许多（但不是所有）病例出现了过敏表现，如发热、皮疹和嗜酸性粒细胞增多。自身抗体通常不存在。
Gemifloxacin (jem" i flox' a sin), like other fluoroquinolones, is associated with a low rate (1% to 7%) of serum enzyme elevations during therapy, although this rate may be slightly higher than occurs with placebo or comparative agents. These abnormalities are generally mild, asymptomatic and transient, resolving even with continuation of therapy. Too few cases of hepatotoxicity due to gemifloxacin have been reported to provide a reliable description of its clinical features and course. However, the liver injury due to the fluoroquinolones appears to be a class effect, and gemifloxacin injury appears to share these characteristics. It is a far less common cause of liver injury than ciprofloxacin, levofloxacin or moxifloxacin, but cases have been reported. In general, fluoroquinone hepatotoxicity is marked by a short time to onset (a few days to 3 weeks); often presenting abruptly with marked nausea, fatigue, abdominal pain and jaundice. The pattern of serum enzyme elevations can be either hepatocellular or cholestatic, and cases with the shorter times to onset are usually more hepatocellular with markedly elevated ALT levels, and occasionally, with rapid worsening of prothrombin time and signs of hepatic failure. The onset of illness may occur a few days after the medication is stopped. Many (but not all) cases have had allergic manifestations with fever, rash and eosinophilia. Autoantibodies are usually not present.
Gemifloxacin and its metabolites are excreted via dual routes of excretion.Following oral administration of gemifloxacin to healthy subjects, a mean (± SD) of 61 ± 9.5% of the dose was excreted in the feces and 36 ± 9.3% in the urine as unchanged drug and metabolites. The mean (± SD) renal clearance following repeat doses of 320 mg was approximately 11.6 ± 3.9 L/hr (range 4.6-6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin.
Gemifloxacin, given as an oral tablet, is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of gemifloxacin were observed between 0.5 and 2 hours following oral tablet administration and the absolute bioavailability of the 320 mg tablet averaged approximately 71% (95% CI 60%-84%). Following repeat oral doses of 320 mg to healthy subjects, the mean + or - SD maximal gemifloxacin plasma concentrations (Cmax) and systemic drug exposure (AUC (0-24)) were 1.61 + or - 0.51 ug/mL (range 0.70-2.62 ug/mL) and 9.93 + or - 3.07 ug.hr/mL (range 4.71-20.1 ug.hr/mL), respectively. In patients with respiratory and urinary tract infections (n=1423), similar estimates of systemic drug exposure were determined using a population pharmacokinetics analysis (geometric mean AUC (0-24), 8.36 ug.hr/mL; range 3.2 -47.7 ug.hr/mL).
Novel Fluoroquinolone Antibacterial Agents Containing Oxime-Substituted (Aminomethyl)pyrrolidines: Synthesis and Antibacterial Activity of 7-(4-(Aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro- 4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic Acid (LB20304),1
摘要：
New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C-5-NH2) > F (C-5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C-5-NH2) > naphthyridine = F (C-5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (mu g/mL) of LB20304, compound 30, and ciprofloxacin against several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128), Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, and 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobacter cloacae P99 (0.008, 0.031, and 0.008), Acinobacter calcoaceticus 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.
[EN] DERIVATIVES OF AMANITA TOXINS AND THEIR CONJUGATION TO A CELL BINDING MOLECULE<br/>[FR] DÉRIVÉS DE TOXINES D'AMANITES ET LEUR CONJUGAISON À UNE MOLÉCULE DE LIAISON CELLULAIRE
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2017046658A1
公开（公告）日：2017-03-23
Derivatives of Amernita toxins of Formula (I), wherein, formula (a) R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, X, L, m, n and Q are defined herein. The preparation of the derivatives. The therapeutic use of the derivatives in the targeted treatment of cancers, autoimmune disorders, and infectious diseases.
[EN] A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS<br/>[FR] CONJUGUÉ D'UN AGENT CYTOTOXIQUE À UNE MOLÉCULE DE LIAISON CELLULAIRE AVEC DES LIEURS RAMIFIÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020257998A1
公开（公告）日：2020-12-30
Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.
[EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
申请人：HANGZHOU DAC BIOTECH CO LTD
公开号：WO2020006722A1
公开（公告）日：2020-01-09
A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.
The present application provides compounds of formula: Methods of using these compounds for killing bacterial growth and treating bacterial infections are also provided.
The present description relates to fused polycyclic 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae or N. meningitides. A compound of Formula (la), Formula (lb) or Formula (Ic), or a form thereof, wherein the dashed lines represent one or more double bonds optionally present where allowed by available valences.
