Quantitative structure-property relationships of camptothecins in humans

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.