Metabolism pathway of vinorelbine (Navelbine®) in human: Characterisation of the metabolites by HPLC–MS/MS

Graeve, J. De; Heugen, J.C. Van; Zorza, Grégoire; Fahy, Jacques; Puozzo, C.

doi:10.1016/j.jpba.2007.12.006

Cited by 26 publications

(24 citation statements)

References 20 publications

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“…Its metabolism has been elucidated and only 4-O-deacetylvinorelbine (DVRL) has been found active (21)(22)(23)(24). Both VRL and DVRL are mostly eliminated via the bile, and only limited amounts are excreted in urine (20,25).…”

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confidence: 99%

Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer

Briasoulis

Pappas

Puozzo

et al. 2009

Clinical Cancer Research

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Aim: To determine the safe dose range and pharmacokinetics of metronomic oral vinorelbine and obtain preliminary data on biomarkers and efficacy in patients with advanced cancer. Methods: Successive cohorts of patients received escalated doses of oral vinorelbine given thrice a week until disease progression, unacceptable toxicity (UT), or consent withdrawal. UT was any grade 4 toxicity, or grade 2 or 3 toxicity that would result to longer than 2-week break during the first 2 months of treatment. Blood samples were collected for pharmacokinetics and quantification of angiogenesis regulatory proteins. Results: Sixty-two patients (median age, 60 years) enrolled at six dose levels from 20 to 70 mg and received treatment for median 12.25 weeks (range, 2-216+). Unacceptable toxicity occurred in two of six patients treated at 60 mg (leucopenia grade 4 and epistaxis grade 2) and in one at 70 mg (leucopenia grade 2). The upper metronomic dose was 50 mg. Objective antitumor response documented in eight cases and 32% of patients experienced disease stability for minimum 6 months. Three responders (renal cancer, medullary thyroid carcinoma, and Kaposi sarcoma) received nonstop treatment for over 3 years without overt toxicity. Low pretreatment levels of circulating interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor were found predictors of efficacy. Steady-state concentrations of vinorelbine and its active metabolite ranged from 0.5 to 1.5 ng/mL. Conclusions: Metronomic administration of oral vinorelbine is feasible at doses up to 50 mg thrice a week and can yield sustainable antitumor activity without overt toxicity, probably through antiangiogenic mechanism. Further clinical investigation is warranted. (Clin Cancer Res 2009;15(20):6454-61)

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confidence: 99%

Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer

Briasoulis

Pappas

Puozzo

et al. 2009

Clinical Cancer Research

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“…58 A vinorelbina é comercializada na forma para administração endovenosa, mas em alguns países é vendida para uso oral. 77 Na formulação oral, a vinorelbina é absorvida rapidamente, entre 1:30 a 3 h, com meia-vida de 4 h. Alimentos não interferem na sua farmacocinética. Portanto, apresenta grande vantagem de conveniência e facilidade de administração ao paciente.…”

Section: Interações Com Microtúbulosunclassified

Química e farmacologia de quimioterápicos antineoplásicos derivados de plantas

Brandão¹,

David²,

Couto³

et al. 2010

Quím. Nova

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Recebido em 11/9/09; aceito em 2/2/10; publicado na web em 18/6/10 CHEMISTRY AND PHARMACOLOGY OF ANTINEOPLASIC CHEMOTERAPEUTICAL DERIVATIVES FROM PLANTS. This review demonstrates the importance of plants as sources of molecules used in anticancer therapies. The approach is performed by relating the active molecules to their origins, details, mechanisms of action, structure-activity relationship and chemical characteristics of chemotherapeutical medicines. It was also described the development of anticancer agents from plants by the pharmaceutical industry and the difficulties to release these compounds as a trademark. These include the well known paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, vindesine, etoposide, teniposide, and other molecules that are undergoing clinical trials.Keywords: plant antineoplasics; chemotherapic; cancer. INTRODUÇÃOSubstâncias orgânicas originadas de fontes naturais há muito tempo são utilizadas no tratamento de inúmeras enfermidades no ser humano. Grande parte dos medicamentos encontrados no mercado é derivada direta ou indiretamente de vegetais, micro-organismos, organismos marinhos, vertebrados e invertebrados terrestres.1,2 Analisando os medicamentos disponibilizados no mercado entre 1981 e 2002, observa-se que 28% destes possuem princípios ativos isolados de produtos naturais ou semissintéticos, ao passo que 24% são sintéticos com grupos farmacofóricos baseados em estruturas de produtos naturais. Portanto, mais da metade dos novos medicamentos lançados no referido período são derivados de produtos naturais, mostrando que essa fonte é muito importante nos estudos de desenvolvimento de novos medicamentos. 1,3 Os vegetais representam as maiores fontes de substâncias ativas que podem ser usadas na terapêutica, devido à grande diversidade estrutural de metabólitos produzidos e, talvez, a fonte mais antiga de medicamentos para o homem. Na busca de novos medicamentos originados de plantas são envolvidos diversos conhecimentos que vão desde aspectos agronômicos, botânicos, químicos, farmacológicos e toxicológicos. 4 Metodologias recentes cada vez mais modernas de isolamento e identificação de compostos de fontes naturais têm propiciado aumento no número de novas estruturas químicas bioativas para inúmeras indicações terapêuticas. Paralelo a esse progresso, desenvolveram-se métodos de screening biológicos automatizados (High Throughput Screening -HTS) que permitem testar in vitro milhares de substân-cias frente a alvos biológicos específicos em curto espaço de tempo.De acordo com Newman, 3 medicamentos derivados de produtos naturais são capazes de tratar 87% das enfermidades humanas categorizadas, incluindo as indicadas como antibacterianas, anticoagulantes, antiparasitárias, imunossupresoras e anticancerígenas. Esta última classe de medicamentos teve 1/3 do mercado em 2002 representado apenas por dois grupos de quimioterápicos derivados de produtos naturais, sendo que os taxanos e derivados da camptotecina representam cerca de U$ 3 bilhões de dólares. 2,5,6A busca por me...

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“…De Graeve et al (2008) have described the MS/MS fragmentation pathways of vinorelbine and its metabolites extensively. The molecular mass of our synthesized product was determined and the MS/MS spectra of vinorelbine and the synthesised product were compared with the spectra published by De Graeve et al (2008) The concentration of synthetic 4-O-deacetylvinorelbine in the methanolic solution was determined by HPLC with UV detection at 280 nm according to the method published by Van Tellingen et al (1993) using vinorelbine as calibration standard.…”

Section: Syntheses Of 4-o-deacetylvinorelbinementioning

confidence: 99%

The bioanalysis of vinorelbine and 4‐O‐deacetylvinorelbine in human and mouse plasma using high‐performance liquid chromatography coupled with heated electrospray ionization tandem mass–spectrometry

Damen

Lagas

Rosing

et al. 2009

Biomedical Chromatography

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A sensitive, specific and efficient high-performance liquid chromatography/tandem mass spectrometry assay for the simultaneous determination of vinorelbine and its metabolite 4-O-deacetylvinorelbine in human and mouse plasma is presented. Heated electrospray ionization was applied followed by tandem mass spectrometry. A 50 microL plasma aliquot was protein precipitated with acetonitrile-methanol (1:1, v/v) containing the internal standard vinorelbine-d3 and 20 microL volumes were injected onto the HPLC system. Separation was achieved on a 50 x 2.1 mm i.d. Xbridge C(18) column using isocratic elution with 1 mm ammonium acetate-ammonia buffer pH 10.5-acetonitrile-methanol (28:12:60, v/v/v) at a flow rate of 0.4 mL/min. The HPLC run time was 5 min. The assay quantifies both vinorelbine and 4-O-deacetylvinorelbine from 0.1 to 100 ng/mL using sample volumes of only 50 microL. Mouse plasma samples can be quantified using calibration curves prepared in human plasma. Validation results demonstrate that vinorelbine and 4-O-deacetylvinorelbine can be accurately and precisely quantified in human and mouse plasma with the presented method. The assay is now in use to support (pre-)clinical pharmacologic studies with vinorelbine in humans and mice.

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Metabolism pathway of vinorelbine (Navelbine®) in human: Characterisation of the metabolites by HPLC–MS/MS

Cited by 26 publications

References 20 publications

Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer

Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer

Química e farmacologia de quimioterápicos antineoplásicos derivados de plantas

The bioanalysis of vinorelbine and 4‐O‐deacetylvinorelbine in human and mouse plasma using high‐performance liquid chromatography coupled with heated electrospray ionization tandem mass–spectrometry

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