A Quantitative HPLC-UV method for determination of serum sorafenib and sorafenib N-oxide and its application in hepatocarcinoma patients

Miki Simada, Hoshimi Okawa, Takahiro Maejima, Toshiki Yanagi, Kanehiko Hisamichi, Masaki Matsuura, Kazutoshi Akasaka, Masami Tsuchiya, Yasuteru Kondo, Tooru Shimosegawa, Masaru Mori, Masamitsu Maekawa, Hiroyuki Suzuki, Nariyasu Mano

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Sorafenib, an oral multi-kinase inhibitor, has been approved for treatment of advanced renal-cell and hepatocellular carcinoma (HCC). However, 20% of HCC patients taking sorafenib are forced to withdraw due to adverse effects within one month after administration. Orally administered sorafenib is oxidatively metabolized, predominantly by cytochrome P450 3A4 (CYP3A4), in small-intestinal mucosa or liver. We aimed to characterize the CYP3A4-mediated metabolism of sorafenib in HCC patients and explore the contribution of the major metabolite sorafenib N-oxide to adverse effects and therapeutic efficacy. We have therefore developed a method for quantitative determination of sorafenib and its N-oxide in the present study. To optimize the preanalytical procedure, we initially ascertained the solubility of the analytes. Because they are lipophilic, solvents containing more than 40% acetonitrile were required for efficient recovery. The pretreatment procedure that we ultimately developed consists of acetonitrile precipitation, followed by extraction using octadecyl silyl-silica gel to eliminate water-soluble and hydrophilic components of serum. Application of this procedure before HPLC enabled accurate and reproducible quantitation of analytes in a linear range from 0.03 to 30 μ g/mL. After characterizing the peaks in the HPLC-ultraviolet chromatogram obtained from a medicated patient by LC-tandem mass spectrometry, we applied this method to HCC patients taking sorafenib, showing large inter-individual differences in the pharmacokinetic profile. In conclusion, our assay system should be useful for follow-up of patients taking sorafenib and for exploring the association between the pharmacokinetics of sorafenib and its N-oxide and the adverse effects or therapeutic efficacy.

Original languageEnglish
Pages (from-to)103-112
Number of pages10
JournalTohoku Journal of Experimental Medicine
Volume233
Issue number2
DOIs
Publication statusPublished - 2014

Keywords

  • Cytochrome P450 3A4
  • Hepatocellular carcinoma
  • High-performance liquid chromatography-ultraviolet system
  • Sorafenib
  • Sorafenib N-oxide

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'A Quantitative HPLC-UV method for determination of serum sorafenib and sorafenib N-oxide and its application in hepatocarcinoma patients'. Together they form a unique fingerprint.

Cite this