slides
Pharmaceutical and Biomedical Aspects of Topoisomerase I Inhibitors
- Publication date
- 15 November 2000
- Publisher
- Pre-clinical and clinical phannacokinetics plays an important rote in the development of new
anticancer agents and in the refinement of already existing therapies. In clinical studies,
phannacokinetic parameters, including area under the plasma concentration-time curve and/or time
above a certain threshold concentration, have previously been shown to be related to the
phannacodynamic outcomes, such as myelosuppression or anti-tumor response. In order to obtain
reliable phannacokinetic parameters, analytical methodologies have to be developed and validated,
enabling accurate detennination of concentrations of anticancer dmgs in biological matrices. These
methodologies have to be validated in terms of selectivity, precision, accuracy and sensitivity, to
obtain meaningful phannacokinetic results.
During the last decade several analogues of the topoisomerase I inhibitor camptothecin have
entered clinical practice. Topoisomerase I is a nuclear enzyme involved in the replication of DNA, by
fonning a cleavable complex, i.e. the covalent interaction between DNA and the enzyme. The
cleavable complex results in a single strand break of the DNA, resulting in relaxation, followed by
replication and resealing of the break. The camptothecin topoisomerase I inhibitors reversibly
stabilize the cleavable complex, resulting in single·strand DNA breaks and thus termination of
DNA replication, subsequently followed by cell death.
The camptothecin analogues share a pH-dependent reversible conversion between their
pharmacologically active lactone form, which is able to diffuse across cell membranes, and their
inactive ring·opened carboxylate form. The existence of the two forms of the camptothecin
analogues requires quick sample handling at the site of the patient in order to acquire real·time
pharmacokinetic data. In chapter 1, an overview of methodologies for the determination of
camptothecin analogues is described and their applicability for pharmacokinetic analysis is
discussed.
In this thesis, methodologies for the quantitative determination of the topoisomerase I
inhibitors topotecan, 9-aminocamptothecin and lurtotecan are described. The applicability of
these assays is shown in both clinical pharmacokinetic and in vitro studies.