title: LC-MS/MS assay and dog pharmacokinetics of the dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501).
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 N(10)-C(11)/N(10')-C(ll') 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 microg/kg doses for five consecutive days.
authors.affiliation: Department of Oncology, Division of Developmental Oncology Research, Mayo Clinic and Foundation, 200 First Street S.W., Rochester, MN 55905, United States.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Buhrow
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
authors.forename: Renee M
authors.initials: RM
authors.lastname: McGovern
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Covey
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Kobs
authors.forename: Irma M
authors.initials: IM
authors.lastname: Grossi
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004285:Dogs; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*; D051379:Mice; D011485:Protein Binding; D011758:Pyrroles / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D012015:Reference Standards
chemical_list: C423343:1,1'-((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); D001570:Benzodiazepinones; D011758:Pyrroles