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

Pradeep B. Lukka, James W. Paxton, Graham J. Atwell, Philip Kestell, Bruce C. Baguley

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 7min 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 0.001μmol/L and was linear (0.001-0.3μmol/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 Vss (r=0.95; P=2×10-7) exhibited a significant positive correlation with LogD values after intravenous bolus administration to mice. Consequently the plasma mean residence time for each of these five analogues decreased with increasing lipophilicity. There was also a significant positive correlation (r=0.91; P=2×10-7) between LogD values and the brain to plasma AUC ratio indicating the importance of lipophilicity in the distribution of these compounds into the brain tissue.

Original languageEnglish (US)
Pages (from-to)9-16
Number of pages8
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume63
DOIs
StatePublished - Apr 7 2012

Fingerprint

Pharmacokinetics
Derivatives
Brain
Plasmas
Pharmaceutical Preparations
Assays
Tissue
Plasma (human)
Metabolism
Intravenous Administration
Liver
Antineoplastic Agents
Toxicology
Area Under Curve
Kidney
Lung
DNA

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Pharmaceutical Science
  • Drug Discovery
  • Spectroscopy
  • Clinical Biochemistry

Cite this

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. / Lukka, Pradeep B.; Paxton, James W.; Atwell, Graham J.; Kestell, Philip; Baguley, Bruce C.

In: Journal of Pharmaceutical and Biomedical Analysis, Vol. 63, 07.04.2012, p. 9-16.

Research output: Contribution to journalArticle

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