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

LC?MS/MS assay and dog pharmacokinetics of the dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501)
24 May 2006
Sarah A. Buhrow, Joel M. Reid, Lee Jia, Renee M. McGovern, Joseph M. Covey, Dean J. Kobs, Irma M. Grossi and Matthew M. Ames
Journal of Chromatography
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 ?g/kg doses for five consecutive days.
Keywords: LC/MS/MS; Pharmacokinetics; Anticancer agents; Benzodiazepine
A subscription is required to view the complete article.