In vitro and in vivo metabolic investigation of the Palbociclib by UHPLC-Q-TOF/MS/MS and in silico toxicity studies of its metabolites

Chavan, Balasaheb B.; Tiwari, Sanjay; Shankar, G.; Nimbalkar, Rakesh D.; Garg, Prabha; Srinivas, R.; Talluri, M.V.N. Kumar

doi:10.1016/j.jpba.2018.05.008

Cited by 41 publications

(20 citation statements)

References 19 publications

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“…The other fragment ions at m/ z 421 (loss of C 3 H 8 NO from m/ z 495), m/ z 381 (loss of CH 2 from m/ z 393), m/ z 351 (loss of isopropyl from m/ z 393), m/ z 302 (loss of C 5 H 5 N from m/ z 381), m/ z 260 (loss of C 6 H 5 N from m/ z 351), m/ z 184 (loss of C 8 H 5 F 2 N 2 from m/ z 393), m/ z 86 (due to ethylazetidine) and m/ z 58 (due to methylaziridine) were generated due to further fragmentation of M2 and M3 metabolites. The fragment ions created at m/ z 86 and m/ z 58 confirms the presence of the piperazine ring in abemaciclib . Additionally, Kadi et al observed only one hydroxylated metabolite at the piperazine ring in RLM and as per his report, this metabolite is mainly responsible for the bioactivation of abemaciclib …”

Section: Resultsmentioning

confidence: 66%

Update on metabolism of abemaciclib: In silico, in vitro, and in vivo metabolite identification and characterization using high resolution mass spectrometry

Thakkar

Kate

2020

Drug Testing and Analysis

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Abemaciclib was approved by the US Food and Drug Administration in 2015 as an advanced treatment for metastatic breast cancer. Identification and characterization of limited numbers of abemaciclib metabolites have been reported in the literature. Therefore, the current study focused on the investigation of the in vitro and in vivo metabolic fate of abemaciclib using high resolution mass spectrometry. Initially, a vulnerable site of metabolism was predicted by the Xenosite web predictor tool. Later, in vitro metabolites were identified from pooled rat liver microsomes, rat S9 fractions, and human liver microsomes. Finally, in vivo metabolites have been detected in plasma, urine, and feces matrix of male Sprague–Dawley rats. A total of 12 putative metabolites (11 phase I and 1 phase II) of abemaciclib and their metabolic pathways were proposed by considering accurate mass, mass fragmentation pattern, nitrogen rule, and ring double bonds of the detected metabolites. Abemaciclib was metabolized via hydroxylation, N‐oxidation, N‐dealkylation, oxidative deamination followed by reduction and sulfate conjugation. In the human liver microsomes, maximum numbers of metabolites (11 metabolites) were observed, from which M7, M8, M9, and M11 were human specific.

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Section: Resultsmentioning

confidence: 66%

Update on metabolism of abemaciclib: In silico, in vitro, and in vivo metabolite identification and characterization using high resolution mass spectrometry

Thakkar

Kate

2020

Drug Testing and Analysis

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“…The further dissociation of the product ion at m/z 273 yielded fragments at m/z 231 (loss of C 3 H 6 ) and 216 (loss of C 4 H 9 ) due to subsequent removal of the alkyl side chain. Neutral loss of the aziridine ring from m/z 216 fragment generated a characteristic ion at m/z 176 and it also confirms the presence of a piperazine ring . In addition, further dissociation of m/z 216 may form m/z 204 and 188 ions due to the formation of pyrrolidine and an azetidine ring from the piperazine ring structure, respectively.…”

Section: Resultsmentioning

confidence: 73%

In silico, in vitro and in vivo metabolite identification of brexpiprazole using ultra‐high‐performance liquid chromatography/quadrupole time‐of‐flight mass spectrometry

Thakkar

Kate

2019

Rapid Comm Mass Spectrometry

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Rationale:Brexpiprazole is a novel serotonin-dopamine activity modulator approved by the USFDA in July 2015 for the treatment of schizophrenia and as an adjunctive therapy with other antidepressants for major depressive disorder in adults. However, limited numbers of metabolites are reported in the literature for brexpiprazole. Our prime intent behind this study is to revisit metabolite profiling of brexpiprazole and to identify and characterize all possible in vitro and in vivo metabolites.Methods: Firstly, the site of metabolism for brexpiprazole was predicted by a Xenosite web predictor model. Secondly, in vitro metabolite profiling was performed by incubating the drug individually with rat liver microsomes, human liver microsomes and rat S9 fraction at 37°C for 1 h in incubator shaker. Finally, for in vivo metabolite identification, a 50 mg kg −1 dose of brexpiprazole was administered to male Sprague-Dawley rats and the presence of various metabolites was confirmed in rat plasma, urine and feces. Results:The predicted atomic site of metabolism was obtained as a color gradient by the Xenosite web predictor tool and, from this study, probable metabolites were listed. In total, 14 phase I and 2 phase II metabolites were identified and characterized in the in vitro and in vivo matrices using ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UHPLC/ QTOF-MS/MS). The majority of metabolites were found in the sample incubated with human liver microsomes and in rat urine, while in the other matrices only a few metabolites were detected. Conclusions:All the 16 metabolites were identified and characterized using UHPLC/QTOF-MS/MS. The study revealed that brexpiprazole is metabolized via hydroxylation,

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“…The association between pulmonary disease and antineoplastic drugs is well known, although its pathogenesis is complex, multifactorial, and dependent on different mechanisms [17, 18]. Although 14 metabolites have been identified in palbociclib, none have toxicity potential [19]. With no biomarkers currently available to predict toxicity, the identification of palbociclib-induced toxicity must rely on a diagnosis of exclusion to rule out pulmonary infections, lymphangitis carcinomatosis, and cardiogenic pulmonary edema.…”

Section: Discussionmentioning

confidence: 99%

New Drugs, Old Toxicities: Pneumonitis Related to Palbociclib – A Case Report

et al. 2019

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Background: Palbociclib is a specific inhibitor of cyclin-dependent kinases 4 and 6 that is approved for the treatment of advanced or metastatic breast cancer patients. Despite a good toxicity profile in pivotal trials, where asymptomatic neutropenia was the main adverse effect, its wider use in clinical practice may show less prevalent but serious toxicities. Case Presentation: Here, we describe a case of pneumonitis due to palbocicblib. A 57-year-old female with breast cancer with bone metastasis presented dyspnea at rest 3 months after beginning treatment with palbociclib and letrozole. Palbociclib-induced pneumonitis was considered the most probable cause after ruling out all alternatives, and the patient was successfully treated with steroids and showed complete remission. Conclusions: In summary, we present a well-documented case report of pneumonitis related to palbociclib. However, the mechanism of toxicity is still unknown, and there are as yet no reliable biomarkers to predict toxicity with cyclin-dependent kinase 4/6 inhibitors. In this case report, we alert physicians about new drugs that can provoke old toxicities.

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In vitro and in vivo metabolic investigation of the Palbociclib by UHPLC-Q-TOF/MS/MS and in silico toxicity studies of its metabolites

Cited by 41 publications

References 19 publications

Update on metabolism of abemaciclib: In silico, in vitro, and in vivo metabolite identification and characterization using high resolution mass spectrometry

Update on metabolism of abemaciclib: In silico, in vitro, and in vivo metabolite identification and characterization using high resolution mass spectrometry

In silico, in vitro and in vivo metabolite identification of brexpiprazole using ultra‐high‐performance liquid chromatography/quadrupole time‐of‐flight mass spectrometry

New Drugs, Old Toxicities: Pneumonitis Related to Palbociclib – A Case Report

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