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Development and validation of a quantification method for cucurbitacins E and I in rat plasma: Application to population pharmacokinetic studies

Lanchoti Fiori, GM; D’Agate, S; Rocha, A; Soares Pereira, AM; Della Pasqua, O; Peporine Lopes, N; (2017) Development and validation of a quantification method for cucurbitacins E and I in rat plasma: Application to population pharmacokinetic studies. Journal of Pharmaceutical and Biomedical Analysis , 144 pp. 99-105. 10.1016/j.jpba.2017.02.021. Green open access

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Abstract

Cucurbitacin E is a potential drug candidate due to its anticancer activity, recognition of its molecular targets, and synergism with other drugs used for cancer treatment. However, the use of cucurbitacin E in clinical practice is not possible because of important knowledge gaps in its preclinical and clinical pharmacokinetic characteristics. Cucurbitacin E is hydrolyzed to cucurbitacin I in plasma and in human liver microsomes. The aim of this study was to evaluate the population pharmacokinetics of cucurbitacin E and of its metabolite cucurbitacin I in rats. The method for the sequential analysis of cucurbitacins E and I in rat plasma was developed using LC-MS/MS. Plasma aliquots of 50 μL were deproteinized with acetonitrile and clobazam was added as internal standard. The extracts were injected into an RP-18 column and eluted with a mobile phase consisting of a mixture of acetonitrile:water:methanol (32:35:33, v/v/v). The method was precise and accurate, showing linearity in the range of 1–100 ng cucurbitacin E/mL plasma and of 0.4–200 ng cucurbitacin I/mL plasma. The method was applied to the pharmacokinetic evaluation of cucurbitacin E administered intravenously to male Wistar rats (1 mg/kg). Serial blood samples were collected up to 24 h after administration. The plasma concentrations of cucurbitacin E were quantified up to 16 h, while the plasma concentrations of cucurbitacin I remained below the limit of quantification. A population pharmacokinetic model was developed for cucurbitacin E using the NONMEM program, with adequate goodness of fit and predictive performance. The following pharmacokinetic parameters were obtained: release time of 0.45 h, volume of distribution of 27.22 L, clearance of 4.13 L/h, and elimination half-life of 4.57 h.

Type: Article
Title: Development and validation of a quantification method for cucurbitacins E and I in rat plasma: Application to population pharmacokinetic studies
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jpba.2017.02.021
Publisher version: http://dx.doi.org/10.1016/j.jpba.2017.02.021
Language: English
Additional information: © 2017 Elsevier B.V. All rights reserved.This manuscript version is made available under a Creative Commons Attribution Non-commercial Non-derivative 4.0 International license (CC BY-NC-ND 4.0). This license allows you to share, copy, distribute and transmit the work for personal and non-commercial use providing author and publisher attribution is clearly stated. Further details about CC BY licenses are available at https://creativecommons.org/licenses/. Access may be initially restricted by the publisher.
Keywords: Cucurbitacin E; Cucurbitacin I; rats; LC–MS/MS; Population pharmacokinetics
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1542458
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