LC-MS/MS assay and dog pharmacokinetics of the dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501)

Sarah A. Buhrow, Joel M Reid, Lee Jia, Renee M. McGovern, Joseph M. Covey, Dean J. Kobs, Irma M. Grossi, Matthew M. Ames

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501) has potent in vitro cytotoxicity and in vivo antitumor activity. SJG-136 binds in the minor groove of DNA and produces G-G interstrand cross-links via reactive N10-C11/N10′-Cll′ imine/carbinolamine moieties. We have developed a sensitive, specific liquid chromatography tandem mass spectrometry (LC/MS/MS) method for the quantitative determination of SJG-136 in plasma. SJG-136 was isolated by solid phase extraction through a C8 column, reverse-phase HPLC separation was accomplished on a C18 column with isocratic elution and MS/MS detection, monitoring the m/z 557-m/z 476 transition after electrospray ionization. The linear range and lower limit of quantitation from plasma standard curves were 2.8-1800 nM, and 5 nM, respectively. SJG-136 plasma protein binding was species-dependent. Values of the unbound fraction in human, rat and mouse were 25%, 16.2% and <1%, respectively. Protein binding was saturable in dog plasma where the unbound fraction increased from 10.8% to 22.3% over a 22-720 nM concentration range. SJG-136 pharmacokinetics after a single intravenous dose were best fit to a two-compartment open model with elimination half-life and plasma clearance values of 97 min and 6.1 mL/min/kg, respectively. SJG-136 did not accumulate in plasma following intravenous administration of 1.0 μg/kg doses for five consecutive days.

Original languageEnglish (US)
Pages (from-to)56-62
Number of pages7
JournalJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Volume840
Issue number1
DOIs
StatePublished - Aug 7 2006

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1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione)
Pharmacokinetics
Assays
Dogs
Plasmas
Protein Binding
Electrospray ionization
Imines
Liquid chromatography
Cytotoxicity
pyrrolo(2,1-c)(1,4)benzodiazepine
Solid Phase Extraction
Phase separation
Tandem Mass Spectrometry
Mass spectrometry
Rats
Blood Proteins
Liquid Chromatography
Intravenous Administration
Half-Life

Keywords

  • Anticancer agents
  • Benzodiazepine
  • LC/MS/MS
  • Pharmacokinetics

ASJC Scopus subject areas

  • Biochemistry

Cite this

LC-MS/MS assay and dog pharmacokinetics of the dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501). / Buhrow, Sarah A.; Reid, Joel M; Jia, Lee; McGovern, Renee M.; Covey, Joseph M.; Kobs, Dean J.; Grossi, Irma M.; Ames, Matthew M.

In: Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, Vol. 840, No. 1, 07.08.2006, p. 56-62.

Research output: Contribution to journalArticle

Buhrow, Sarah A. ; Reid, Joel M ; Jia, Lee ; McGovern, Renee M. ; Covey, Joseph M. ; Kobs, Dean J. ; Grossi, Irma M. ; Ames, Matthew M. / LC-MS/MS assay and dog pharmacokinetics of the dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501). In: Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences. 2006 ; Vol. 840, No. 1. pp. 56-62.
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T1 - LC-MS/MS assay and dog pharmacokinetics of the dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501)

AU - Buhrow, Sarah A.

AU - Reid, Joel M

AU - Jia, Lee

AU - McGovern, Renee M.

AU - Covey, Joseph M.

AU - Kobs, Dean J.

AU - Grossi, Irma M.

AU - Ames, Matthew M.

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N2 - The dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501) has potent in vitro cytotoxicity and in vivo antitumor activity. SJG-136 binds in the minor groove of DNA and produces G-G interstrand cross-links via reactive N10-C11/N10′-Cll′ imine/carbinolamine moieties. We have developed a sensitive, specific liquid chromatography tandem mass spectrometry (LC/MS/MS) method for the quantitative determination of SJG-136 in plasma. SJG-136 was isolated by solid phase extraction through a C8 column, reverse-phase HPLC separation was accomplished on a C18 column with isocratic elution and MS/MS detection, monitoring the m/z 557-m/z 476 transition after electrospray ionization. The linear range and lower limit of quantitation from plasma standard curves were 2.8-1800 nM, and 5 nM, respectively. SJG-136 plasma protein binding was species-dependent. Values of the unbound fraction in human, rat and mouse were 25%, 16.2% and <1%, respectively. Protein binding was saturable in dog plasma where the unbound fraction increased from 10.8% to 22.3% over a 22-720 nM concentration range. SJG-136 pharmacokinetics after a single intravenous dose were best fit to a two-compartment open model with elimination half-life and plasma clearance values of 97 min and 6.1 mL/min/kg, respectively. SJG-136 did not accumulate in plasma following intravenous administration of 1.0 μg/kg doses for five consecutive days.

AB - The dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501) has potent in vitro cytotoxicity and in vivo antitumor activity. SJG-136 binds in the minor groove of DNA and produces G-G interstrand cross-links via reactive N10-C11/N10′-Cll′ imine/carbinolamine moieties. We have developed a sensitive, specific liquid chromatography tandem mass spectrometry (LC/MS/MS) method for the quantitative determination of SJG-136 in plasma. SJG-136 was isolated by solid phase extraction through a C8 column, reverse-phase HPLC separation was accomplished on a C18 column with isocratic elution and MS/MS detection, monitoring the m/z 557-m/z 476 transition after electrospray ionization. The linear range and lower limit of quantitation from plasma standard curves were 2.8-1800 nM, and 5 nM, respectively. SJG-136 plasma protein binding was species-dependent. Values of the unbound fraction in human, rat and mouse were 25%, 16.2% and <1%, respectively. Protein binding was saturable in dog plasma where the unbound fraction increased from 10.8% to 22.3% over a 22-720 nM concentration range. SJG-136 pharmacokinetics after a single intravenous dose were best fit to a two-compartment open model with elimination half-life and plasma clearance values of 97 min and 6.1 mL/min/kg, respectively. SJG-136 did not accumulate in plasma following intravenous administration of 1.0 μg/kg doses for five consecutive days.

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KW - Pharmacokinetics

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