Single-dose pharmacokinetics of the DNA-binding bioreductive agent NLCQ-1 (NSC 709257) in CD2F1 mice

Joel M. Reid, David P. Squillace, Matthew M. Ames

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

NLCQ-1 (NSC 709257) is a weak DNA-binding bioreductive antiproliferative agent, with potent in vitro antiproliferative activity against rodent and human tumor cell lines under aerobic and anaerobic conditions. Interest in this quinoline analog is based in part on its in vivo synergistic antitumor effect with radiotherapy or chemotherapy against mouse tumors and human xenografts. A sensitive, specific HPLC method was developed to measure NLCQ-1 in biological fluids. Calibration curves were linear in the range 10.4-667 ng/ml and the lower limit of quantitation was 10.4 ng/ml in plasma. NLCQ-1 was stable in organic solvents, buffered solutions and human plasma for 24 h at 37°C. NLCQ-1 was unstable in rodent and dog plasma when incubated for longer than 10 h. NLCQ-1 human plasma protein binding was high (about 99%), and included binding to both α1-acid glycoprotein and serum albumin. The plasma elimination of NLCQ-1 in mice after a 10-mg/kg intravenous bolus dose was described by a two-compartment open model with t1/2β, Vss, and ClTB values of 41.3 min, 2.04 1/kg and 69.9 ml/min per kg, respectively. NLCQ-1 had high (85%) intraperitoneal and modest (28%) oral relative bioavailability. Little of the administered NLCQ-1 dose (6.4%) was excreted in 24-h urine. The mouse pharmacokinetic data suggested that oral administration may achieve plasma concentration and systemic exposure similar to those observed after intravenous administration of NLCQ-1.

Original languageEnglish (US)
Pages (from-to)483-487
Number of pages5
JournalCancer chemotherapy and pharmacology
Volume51
Issue number6
DOIs
StatePublished - Jun 1 2003

Keywords

  • Bioreductive compounds
  • DNA
  • HPLC
  • Mice
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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