A rapid LC-MS/MS method for the quantitation of a series of benzonaphthyridine derivatives: application to in vivo pharmacokinetic and lipophilicity studies in drug development

Journal of Pharmaceutical and Biomedical Analysis
Pradeep B LukkaBruce C Baguley

Abstract

Drug lipophilicity is a vital physicochemical parameter that influences drug absorption, distribution, metabolism, excretion and toxicology. A comparative study of a homologous series based on a pharmaceutically active drug represents a powerful approach to the study of the effects of drug lipophilicity. We have developed a rapid and sensitive LC-MS/MS method suitable for such a homologous series and applied it to a series of DNA binding benzonaphthyridine-based antitumour drugs of differing lipophilicity. The method used a gradient elution with a run time of 7 min for simultaneous quantitation of five analogues in a pooled sample. Method validation was carried out in plasma (human and mouse) and mouse tissues (brain, heart, kidney, liver and lung). It had a limit of quantitation of 0.001 μmol/L and was linear (0.001-0.3 μmol/L) in all matrices with acceptable intra- and inter-assay precision and accuracy. This method allowed the pharmacokinetic parameters of these compounds in mice to be related to their lipophilicity as determined by their partition coefficient (LogD). Both the plasma CL (r=0.95; P=2×10⁻⁷) and V(ss) (r=0.95; P=2×10⁻⁷) exhibited a significant positive correlation with LogD values after intravenous bolus admini...Continue Reading

References

Mar 7, 2003·Journal of Medicinal Chemistry·Leslie W DeadyWilliam A Denny
May 19, 2009·Journal of Medicinal Chemistry·Manthena V S VarmaAyman El-Kattan
Sep 24, 2009·Cancer Chemotherapy and Pharmacology·Pradeep B LukkaBruce C Baguley
Feb 16, 2011·Current Topics in Medicinal Chemistry·R Scott Obach
Feb 16, 2011·Current Topics in Medicinal Chemistry·Dennis A Smith
Mar 1, 2010·Expert Opinion on Drug Discovery·Michael J Waring

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