Preliminary pharmacokinetic and bioanalytical studies of SJG-136 (NSC 694501), a sequence-selective pyrrolobenzodiazepine dimer DNA-cross-linking agent

Wilkinson, G.P., Taylor, J.P., Shnyder, S.D., Cooper, P., Howard, P.W., Thurston, D.E., Jenkins, T.C. and Loadman, P.M. (2004) Preliminary pharmacokinetic and bioanalytical studies of SJG-136 (NSC 694501), a sequence-selective pyrrolobenzodiazepine dimer DNA-cross-linking agent. Investigational New Drugs, 22 (3). pp. 231-240. doi:10.1023/B:DRUG.0000026249.97007.60.

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DOI: doi:10.1023/B:DRUG.0000026249.97007.60

Abstract

SJG-136 is a synthetic pyrrolobenzodiazepine (PBD) dimer in which two DNA-alkylating subunits are linked through an inert propanedioxy tether. Biophysical and biochemical studies of SJG-136 have shown a remarkable affinity for DNA and potent cytotoxicity in vitro. On this basis, together with its unique sequence selectivity and interstrand DNA cross-linking activity, SJG-136 has been selected for clinical trials. This study examines the pharmacological characteristics of SJG-136 and provides the first report of pharmacokinetic properties for this agent. A sensitive, selective and reproducible reversed-phase gradient LC/MS assay has been developed for detection and analysis, where a molecular ion (m/z 557.2) is detectable for the SJG-136 parent imine. Fluorescence detection (260 nm excitation, 420 nm emission) gives a limit of sensitivity of 5 nM (2.5 ng ml–1) for analysis of SJG-136 in mouse plasma. Extraction efficiencies from plasma were >65% across a range of concentrations (5–1000 nM). Following administration to mice at the MTD (i.p., 0.2 mg kg–1), high peak plasma concentrations of SJG-136 were seen (C max = 336 nM) at 30 min after dosing. A calculated terminal t 1/2 of 0.98 h and AUC of 0.34 M·h resulted in a clearance rate of 17.7 ml min–1 kg–1. The PBD dimer binds only moderately to proteins (65–75%), and in vitro cytotoxicity studies confirmed IC50 values of 4–30 nM with a panel of human cell lines. This finding demonstrates that plasma concentrations achieved in the mouse are substantially higher than those required to elicit an anti tumour response in vitro. This report forms an important phase in the pre-clinical characterization of the compound.

Item Type:Article
Uncontrolled Keywords:plasma - protein binding - DNA cross-linking - mass spectrometry - HPLC - PBD
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:1886
Journal or Publication Title:Investigational New Drugs
Deposited By:Library Staff
Deposited On:10 Mar 2011 14:37
Last Modified:10 Mar 2011 14:37

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