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

Author(s)

Lanchoti Fiori, Giovana Maria ; D'Agate, Salvatore ; Rocha, Adriana ; Soares Pereira, Ana Maria ; Della Pasqua, O. ; Lopes, Norberto Peporine

• Document type: Journal article
• Source: Journal of Pharmaceutical and Biomedical Analysis; v. 144, p. 7-pg., 2017-09-10.

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 mu L 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 16h, 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. (C) 2017 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 12/14408-9 - Disposition kinetics, plasma protein binding, metabolism in vitro and in vivo of curcubitacins in rats
• Grantee: Giovana Maria Lanchoti Fiori
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/50265-3 - Distribution and metabolism of natural and synthetic xenobiotics: from the comprehension of reactional process to tissue imaging generation
• Grantee: Norberto Peporine Lopes
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants