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  2. Investigation of the effect of plasma albumin levels on regorafenib-induced hepatotoxicity using a validated liquid chromatography-tandem mass spectrometry method

Investigation of the effect of plasma albumin levels on regorafenib-induced hepatotoxicity using a validated liquid chromatography-tandem mass spectrometry method

  • J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Sep 1;1061-1062:220-224. doi: 10.1016/j.jchromb.2017.07.023.
Yi Yun Pang 1 Yeong Lan Tan 1 Han Kiat Ho 2
Affiliations

Affiliations

  • 1 Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
  • 2 Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address: [email protected].
Abstract

Regorafenib is an oral multikinase inhibitor indicated for metastatic colorectal Cancer and gastrointestinal stromal tumour. Due to its extensive plasma protein binding and low calculated hepatic extraction ratio, the hepatotoxicity observed with usage of the drug may be related to its plasma exposure. To investigate the highly dynamic free:bound drug concentration for regorafenib in the plasma, a bioanalytical liquid chromatography-tandem mass spectrometric assay was developed and validated in human plasma. The concentration range of the assay was 2-1000ng/mL. Sample preparation was via protein precipitation using acetonitrile with sorafenib as the internal standard. The supernatant was injected into an ultra-performance liquid chromatographic system coupled to a triple quadrupole mass spectrometer. The analytes were separated on an AQUITY UPLC BEH C18 column (120Å, 1.7μm, 2.1mm×50mm) and eluted with a gradient elution system. The ions were detected in multiple reaction monitoring mode. The linearity, lower limit of quantification, intra-day and inter-day precision and accuracy conformed to FDA guidelines. The validated method was successfully applied to determine the effect of albumin levels in plasma on the extent of protein binding of regorafenib. The results indicated that physiologically-relevant levels of albumin were found to have no significant effect on the extent of protein binding of regorafenib, hence imposing minimal effect on drug disposition.

Keywords

LC–MS/MS; Plasma protein binding; Regorafenib.

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