Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC-MS/MS method for clinical pharmacokinetic application

Jeffrey Roth, Cody J. Peer, Brigitte Widemann, Diane E. Cole, Rachel Ershler, Lee J. Helman, David Schrump, William D. Figg

Research output: Contribution to journalArticle

Abstract

Mithramycin is a neoplastic antibiotic synthesized by various Streptomyces bacteria. It is under investigation as a chemotherapeutic treatment for a wide variety of cancers. Ongoing and forthcoming clinical trials will require pharmacokinetic analysis of mithramycin in humans, both to see if target concentrations are achieved and to optimize dosing and correlate outcomes (response/toxicity) with pharmacokinetics. Two published methods for mithramycin quantitation exist, but both are immunoassays that lack current bioanalytical standards of selectivity and sensitivity. To provide an upgraded and more widely applicable assay, a UPLC-MS/MS method for quantitation of mithramycin in human plasma was developed. Solid-phase extraction allowed for excellent recoveries (>90%) necessary for high throughput analyses on sensitive instrumentation. However, a ~55% reduction in analyte signal was observed as a result of plasma matrix effects. Mithramycin and the internal standard chromomycin were separated on a Waters Acquity BEH C18 column (2.1×50mm, 1.7μm) and detected using electrospray ionization operated in the negative mode at mass transitions m/z 1083.5→268.9 and 1181.5→269.0, respectively, on an AB Sciex QTrap 5500. The assay range was 0.5-500ng/mL and proved to be linear (r2>0.996), accurate (≤10% deviation), and precise (CV

Original languageEnglish (US)
Pages (from-to)95-101
Number of pages7
JournalJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Volume970
DOIs
StatePublished - Sep 6 2014
Externally publishedYes

Fingerprint

Plicamycin
Plasma (human)
Pharmacokinetics
High Pressure Liquid Chromatography
Assays
Chromomycins
Electrospray ionization
Solid Phase Extraction
Streptomyces
Immunoassay
Toxicity
Bacteria
Throughput
Clinical Trials
Anti-Bacterial Agents
Plasmas
Recovery
Water
Neoplasms

Keywords

  • Mithramycin
  • Tandem mass spectrometry
  • Ultra-HPLC

ASJC Scopus subject areas

  • Biochemistry
  • Analytical Chemistry
  • Cell Biology
  • Clinical Biochemistry

Cite this

Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC-MS/MS method for clinical pharmacokinetic application. / Roth, Jeffrey; Peer, Cody J.; Widemann, Brigitte; Cole, Diane E.; Ershler, Rachel; Helman, Lee J.; Schrump, David; Figg, William D.

In: Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, Vol. 970, 06.09.2014, p. 95-101.

Research output: Contribution to journalArticle

Roth, Jeffrey ; Peer, Cody J. ; Widemann, Brigitte ; Cole, Diane E. ; Ershler, Rachel ; Helman, Lee J. ; Schrump, David ; Figg, William D. / Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC-MS/MS method for clinical pharmacokinetic application. In: Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences. 2014 ; Vol. 970. pp. 95-101.
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