Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.
Lapatinib, an oral breast cancer drug, has recently been reported to be a mechanism-based inactivator of cytochrome P450 (P450) 3A4 and also an idiosyncratic hepatotoxicant. It was suggested that formation of a reactive quinoneimine metabolite was involved in mechanism-based inactivation (MBI) and/or hepatotoxicity. We investigated the mechanism of MBI of P450 3A4 by lapatinib. Liquid chromatography-mass spectrometry analysis of P450 3A4 after incubation with lapatinib did not show any peak corresponding to irreversible modifications. The enzymatic activity inactivated by lapatinib was completely restored by the addition of potassium ferricyanide. These results indicate that the mechanism of MBI by lapatinib is quasi-irreversible and mediated via metabolic intermediate complex (MI complex) formation. This finding was verified by the increase in a signature Soret absorbance at approximately 455 nm. Two amine oxidation products of the metabolism of lapatinib by P450 3A4 were characterized: N-hydroxy lapatinib (M3) and the oxime form of N-dealkylated lapatinib (M2), suggesting that a nitroso or another related intermediate generated from M3 is involved in MI complex formation. In contrast, P450 3A5 was much less susceptible to MBI by lapatinib via MI complex formation than P450 3A4. In addition, P450 3A5 had a significantly lower ability than 3A4 to generate M3, consistent with N-hydroxylation as the initial step in the pathway to MI complex formation. In conclusion, our results demonstrate that the primary mechanism for MBI of P450 3A4 by lapatinib is not irreversible modification by the quinoneimine metabolite, but quasi-irreversible MI complex formation mediated via oxidation of the secondary amine group of lapatinib.
Lapatinib undergoes extensive metabolism in humans to numerous oxidated and N- and O-dealkylated products. In vitro studies using human hepatocytes and microsomes indicated that lapatinib is primarily metabolised by CYP3A4 and CYP3A5, with smaller contributions from CYP2C8. Additional studies indicated that CYP1A2, 2D6, 2C9 and 2C19 may also be involved, but to a lesser extent. The most prominent metabolites are the carboxylic acid GW42393 and the O-dealkylated phenol GW690006. N-oxidation of the secondary aliphatic amine produced a cascade of about 8 minor metabolites. Relative to parent drug, GW690006 produced approximately equipotent inhibition of ErbB1-dependent tumour cell growth in vitro, but was approximately 100-fold less potent in ErbB2- dependent tumour cells. GW342393 was found to be approximately 40-fold less potent than parent drug in both ErbB1- and ErbB2-dependent tumour cells. They are unlikely to contribute to the biological activity of lapatinib.
Lapatinib, an oral tyrosine kinase inhibitor used for breast cancer, has been reported to cause idiosyncratic hepatotoxicity. Recently, it has been found that lapatinib forms a metabolite-inhibitor complex (MIC) with CYP3A4 via the formation of an alkylnitroso intermediate. Because CYP3A5 is highly polymorphic compared with CYP3A4 and also oxidizes lapatinib, we investigated the interactions of lapatinib with CYP3A5. Lapatinib inactivated CYP3A5 in a time-, concentration-, and NADPH-dependent manner using testosterone as a probe substrate with K(I) and k(inact) values of 0.0376 mM and 0.0226 min(-1), respectively. However, similar results were not obtained when midazolam was used as the probe substrate, suggesting that inactivation of CYP3A5 by lapatinib is site-specific. Poor recovery of CYP3A5 activity postdialysis and the lack of a Soret peak confirmed that lapatinib does not form a MIC with CYP3A5. The reduced CO difference spectrum further suggested that a large fraction of the reactive metabolite of lapatinib is covalently adducted to the apoprotein of CYP3A5. GSH trapping of a reactive metabolite of lapatinib formed by CYP3A5 confirmed the formation of a quinoneimine-GSH adduct derived from the O-dealkylated metabolite of lapatinib. In silico docking studies supported the preferential formation of an O-dealkylated metabolite of lapatinib by CYP3A5 compared with an N-hydroxylation reaction that is predominantly catalyzed by CYP3A4. In conclusion, lapatinib appears to be a mechanism-based inactivator of CYP3A5 via adduction of a quinoneimine metabolite.
Metabolism of lapatinib was assessed both quantitatively and qualitatively in the plasma and excreta of rats (10 mg/kg), dogs (10 mg/kg), mice (30 mg/kg) and humans (250 mg) following a single oral administration of (14)C-lapatinib. In general, (14)C-lapatinib was primarily metabolized, secreted in the bile and eliminated in the feces. In the nonclinical and clinical metabolism studies, urine samples were not analyzed due to the low percentage of the dose excreted by this route. In plasma, (14)C-lapatinib represented the largest single component in all species. Lapatinib was more extensively metabolised in male rats than in female rats, however the metabolic profiles were similar. In dogs and humans, 14C-lapatinib was the only quantifiable peak present. In humans, lapatinib accounted for only approximately half of the radioactivity in the plasma. The remaining radioactivity was attributed to at least 8 metabolites detected by LC-MS but below the limit of radiochemical quantification (approximately 5% of the total radioactivity in pooled plasma). These metabolites were attributed to the N-oxidation cascade that was also observed in vitro as well as in rats and mice. In both mice and rats, only a few of these metabolites were quantifiable in plasma by radiochemical detection, but all were characterized by mass spectrometry. Thus, no unique circulating metabolites were observed in humans
IDENTIFICATION AND USE: Lapatinib is a yellow solid formulated into film-coated tablets. Lapatinib, an inhibitor of human epidermal growth factor receptor type 2 (HER2/ERBB2) and epidermal growth factor receptor (HER1/EGFR/ERBB1) tyrosine kinases, is an antineoplastic agent. It is used in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. It is also used in combination with letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor, and for whom hormonal therapy is indicated. HUMAN EXPOSURE AND TOXICITY: Asymptomatic and symptomatic cases of overdose have been reported. The doses ranged from 2,500 to 9,000 mg daily, the duration varied between 1 and 17 days. Symptoms observed include lapatinib-associated events and in some cases sore scalp, sinus tachycardia (with otherwise normal ECG), and/or mucosal inflammation. At therapeutic doses, hepatotoxicity, manifested as increases in serum concentrations of aminotransferases and bilirubin, has been observed in clinical trials and post-marketing experience with lapatnib. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur within days to several months after initiation of treatment. Women should avoid the use of lapatinib during pregnancy. While there are not adequate and well-controlled studies in pregnant women, lapatinib has been associated with adverse reproductive effects in animals. If used during pregnancy, the patient should be apprised of the potential fetal hazard. ANIMAL STUDIES: While there was no evidence of carcinogenicity in a two year mouse study, increased mortality which was related to skin toxicities was observed in males at 150 and 300 mg/kg/day and in females at 300 mg/kg/day. In a two-year rat carcinogenicity study, increased mortality was observed in males at 500 mg/kg/day and females at 300 mg/kg/day, and was related to skin toxicities. Renal infarcts and papillary necrosis were observed in females from 60 mg/kg/day and 180 mg/kg/day, respectively. An increased incidence of benign hemangioma of the mesenteric lymph nodes was noted in males from 120 mg/kg/day and in females at 180 mg/kg/day but was within background range. The clinical significance of these findings to humans is not known. Lapatinib did not affect male or female rat gonadal function, mating, or fertility at doses up to 120 mg/kg/day in females and up to 180 mg/kg/day in males. Studies in pregnant rats and rabbits revealed no teratogenic effects. However, in rats, minor anomalies (left-sided umbilical artery, cervical rib and precocious ossification) occurred at the maternally toxic dose of 120 mg/kg/day. In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day and abortions at 120 mg/kg/day. At maternally toxic doses, decreased fetal body weights, decreased number of live fetuses and minor skeletal variations were noted. Lapatinib was not clastogenic or mutagenic in a battery of assays including the Chinese hamster chromosome aberration assay, the Ames assay, human lymphocyte chromosome aberration assay and an in vivo rat bone marrow chromosome aberration assay.
Elevations in serum aminotransferase levels are common during lapatinib therapy, occurring in up to half of patients. Values greater than 5 times the upper limit of normal (ULN) occur in 2% to 6% of patients but are usually transient and asymptomatic. Dose adjustments or temporary discontinuations are rarely required for liver test abnormalities.
Since its introduction into clinical use, lapatinib has been linked to several cases of clinically apparent acute liver injury. The clinical features of injury have not been well defined, but the onset is usually within 1 to 3 months of starting lapatinib and the pattern of serum enzyme elevations is typically hepatocellular or mixed (Case 1). Sufficent numbers of reports of liver injury have been made to the Food and Drug Administration such that lapatinib is listed as having hepatotoxicity that can be fatal. The frequency of serious liver injury is estimated to be 0.2%, but is likely higher. Immunoallergic and autoimmune features are uncommon, although genetic studies suggest that lapatinib hepatotoxicity is linked to specific HLA alleles. Most instances are self-limited, but several cases of acute liver failure have been reported with tyrosine kinase receptor inhibitors including imatinib, sunitinib, lapatinib, gefitinib and erlotinib. Recurrence of injury is common with reexposure but may not occur upon switching to another kinase receptor inhibitor.
Likelihood score: B (likely cause of clinically apparent acute liver injury).
Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.
After administration of a single oral dose of (14)C-lapatinib, the predominant route of elimination of drug-related material in the mouse, rat and dog was in the feces, with very little urinary excretion. Most of the dose was eliminated within 48 hours post-dose.
Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (<2%) renal excretion. Recovery of parent lapatinib in feces accounts for a median of 27% (range 3% to 67%) of an oral dose.
Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC values were approximately 3- and 4-fold higher (Cmax approximately 2.5- and 3-fold higher) when administered with a low-fat (5% fat-500 calories) or with a high-fat (50% fat-1,000 calories) meal, respectively.
[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.
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
[EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
申请人：CANCER RESEARCH TECH LTD
公开号：WO2018215798A1
公开（公告）日：2018-11-29
The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.
[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.
