Quantitation of sorafenib and its active metabolite sorafenib N-oxide in human plasma by liquid chromatography–tandem mass spectrometry

Li, Lie; Zhao, Ming; Navid, Fariba; Pratz, Keith W.; Smith, Brett; Rudek, Michelle A.; Baker, Sharyn D.

doi:10.1016/j.jchromb.2010.08.049

Cited by 52 publications

(47 citation statements)

References 12 publications

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“…Plasma was isolated following Ficoll centrifugation and frozen at −20°C until use. Plasma samples obtained during sorafenib therapy were collected on study NCT01578109 and analyzed per previously described methods (16). …”

Section: Methodsmentioning

confidence: 99%

Adaptation to TKI Treatment Reactivates ERK Signaling in Tyrosine Kinase–Driven Leukemias and Other Malignancies

Bruner

Hayley

et al. 2017

Cancer Research

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FLT3 tyrosine kinase inhibitors (TKI) have been tested extensively to limited benefit in acute myeloid leukemia. We hypothesized that FLT3/ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to TKI treatment that are associated with an incomplete response. Here we identified reactivation of ERK signaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3. When these cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abrogated and anti-leukemia effects were more pronounced compared to either drug alone. ERK reactivation was also observed following inhibition of other tyrosine kinase-driven cancer cells, including EGFR-mutant lung cancer, HER2-amplified breast cancer and BCR-ABL leukemia. These studies reveal an adaptive feedback mechanism in tyrosine kinase-driven cancers associated with reactivation of ERK signaling in response to targeted inhibition.

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Section: Methodsmentioning

confidence: 99%

Adaptation to TKI Treatment Reactivates ERK Signaling in Tyrosine Kinase–Driven Leukemias and Other Malignancies

Bruner

Hayley

et al. 2017

Cancer Research

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“…Vesicles from Sf9 cells (Life Technologies) expressing mouse Abcc2 (mAbcc2), rat Abcc2 (rAbcc2), human ABCC2 (ABCC2), human ABCC3 (ABCC3), or human ABCC4 (ABCC4) were incubated with sorafenib (10 µM; Chemie Tek, Indianapolis, IN) or SG (10 µM) for 5 min in the presence or absence of ATP (4 mM) or rifampin (100 µM), then lysed with 0.1 M HCl, and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (20). ATP-dependent transport of sorafenib and SG was determined by subtracting AMP-dependent transport from ATP-dependent transport, with both expressed in pmol/min/mg, after normalization for non-specific transport observed in control vesicles.…”

Section: Methodsmentioning

confidence: 99%

Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b

Vasilyeva

Durmuş

et al. 2015

Cancer Research

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Recently, an efficient liver detoxification process dubbed ‘hepatocyte hopping’ was proposed based on findings with the endogenous compound, bilirubin glucuronide. According to this model, hepatocytic bilirubin glucuronide can follow a liver-to-blood shuttling loop via Abcc3 transporter-mediated efflux and subsequent Oatp1a/1b-mediated liver uptake. We hypothesized that glucuronide conjugates of xenobiotics, such as the anticancer drug sorafenib, can also undergo hepatocyte hopping. Using transporter-deficient mouse models, we show here that sorafenib-glucuronide can be extruded from hepatocytes into the bile by Abcc2 or back into the systemic circulation by Abcc3, and that it can be taken up efficiently again into neighboring hepatocytes by Oatp1a/1b. We further demonstrate that sorafenib-glucuronide excreted into the gut lumen can be cleaved by microbial enzymes to sorafenib which is then reabsorbed, supporting its persistence in the systemic circulation. Our results suggest broad relevance of a hepatocyte shuttling process known as “hepatocyte hopping” – a novel concept in clinical pharmacology - for detoxification of targeted cancer drugs which undergo hepatic glucuronidation, such as sorafenib.

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“…Bone marrow samples were enriched for leukemic blasts by ficoll purification. Trough concentrations of sorafenib and the metabolite sorafenib N-oxide were measured in plasma during sorafenib treatment using a validated analytical method based on liquid chromatography-tandem mass spectrometry (24). All treatments and assessments were approved by the institutional review board and informed consent was obtained from all patients or their legal guardians.…”

Section: Methodsmentioning

confidence: 99%

Emergence of Polyclonal FLT3 Tyrosine Kinase Domain Mutations during Sequential Therapy with Sorafenib and Sunitinib in FLT3-ITD–Positive Acute Myeloid Leukemia

Baker

Zimmerman

Wang

et al. 2013

Clinical Cancer Research

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Purpose To evaluate the clinical activity of sequential therapy with sorafenib and sunitinib in FLT3-ITD-positive AML and monitor the emergence of secondary FLT3 tyrosine kinase domain (TKD) mutations during treatment. Experimental Design Six children with relapsed/refractory AML were treated with sorafenib in combination with clofarabine and cytarabine, followed by single-agent sorafenib if not a candidate for transplantation. Sunitinib was initiated after sorafenib relapse. Bone marrow samples were obtained for assessment of FLT3 TKD mutations by deep amplicon sequencing. The phase of secondary mutations with ITD alleles was assessed by cloning and sequencing of FLT3 exons 14 through 20. Identified mutations were modeled in Ba/F3 cells and the effect of kinase inhibitors on FLT3 signaling and cell viability was assessed. Results Four patients achieved complete remission, but 3 receiving maintenance therapy with sorafenib relapsed after 14–37 weeks. Sunitinib reduced circulating blasts in 2 patients and marrow blasts in 1. Two patients did not respond to sorafenib combination therapy or sunitinib. FLT3 mutations at residues D835 and F691 were observed in sorafenib resistance samples on both ITD-positive and –negative alleles. Deep sequencing revealed low-level mutations and their evolution during sorafenib treatment. Sunitinib suppressed leukemic clones with D835H and F691L mutations, but not D835Y. Cells expressing sorafenib-resistant FLT3 mutations were sensitive to sunitinib in vitro. Conclusions Sunitinib has activity in patients that are resistant to sorafenib and harbor secondary FLT3 TKD mutations. The use of sensitive methods to monitor FLT3 mutations during therapy may allow individualized treatment with the currently available kinase inhibitors.

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Quantitation of sorafenib and its active metabolite sorafenib N-oxide in human plasma by liquid chromatography–tandem mass spectrometry

Cited by 52 publications

References 12 publications

Adaptation to TKI Treatment Reactivates ERK Signaling in Tyrosine Kinase–Driven Leukemias and Other Malignancies

Adaptation to TKI Treatment Reactivates ERK Signaling in Tyrosine Kinase–Driven Leukemias and Other Malignancies

Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b

Emergence of Polyclonal FLT3 Tyrosine Kinase Domain Mutations during Sequential Therapy with Sorafenib and Sunitinib in FLT3-ITD–Positive Acute Myeloid Leukemia

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