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Abstract
To develop quantitative structure property relationships (QSPR) for the pharmacokinetics and the susceptibility to BCRP-mediated efflux of ten drugs in the camptothecin family of topoisomerase I inhibitors.
Pharmacokinetic parameters (total and lactone clearance, total steady-state volume of distribution, and lactone:total area under the curve ratio) and IC50 values of cytotoxicity in both BCRP over-expressing and sensitive cell lines were extracted from the literature. Molecular descriptors were generated for both the lactone and carboxylic acid forms of the drugs using SYBYL and ACD/Labs software. A partial least squares algorithm in SAS was used to construct QSPR models for each of the properties of interest, and final models were validated using leave-one-out cross-validation.
The molecular descriptors calculated for the lactone forms were better correlated with the selected properties than that of the carboxylate forms. Reasonable correlations (R 2 range 0.63-0.99) and good predictive performances (Q 2 range 0.45-0.88) were obtained for all seven QSPR models. Molecular descriptors that contribute to each pharmacokinetic property and susceptibility to BCRP mediated efflux were identified.
QSPR models were successfully constructed for the pharmacokinetics and the susceptibility to BCRP-mediated efflux of the camptothecin analogs. The identified molecular parameters may help guide the synthesis of new camptothecin analogs with improved pharmacokinetic properties and reduced potential for clinical resistance.