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

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 50μL 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 1-100ng cucurbitacin E/mL plasma and of 0.4-200ng cucurbitacin I/mL plasma. The method was applied to the pharmacokinetic evaluation of cucurbitacin E administered intravenously to male Wistar rats (1mg/kg). Serial blood samples were collected up to 24h 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 0.45h, volume of distribution of 27.22L, clearance of 4.13L/h, and elimination half-life of 4.57h.

Cucurbitacin E Chemosensitizes Colorectal Cancer Cells via Mitigating TFAP4/Wnt/β-Catenin Signaling

“…It is very important to understand the in vivo pharmacological properties of any natural compound through in-depth understanding of drug metabolism and pharmacokinetics. The pharmacokinetic results showed that CE (1 mg/kg) was administered intravenously to male Wistar rats with a release time of 0.45 h, clearance of 4.13 L/h, and elimination half-life of 4.57 h . While no data currently exist on the pharmacokinetic profile of oral or intraperitoneal administration of CE in vivo, studies have demonstrated that the priority of the bioavailability was intravenous injection, intraperitoneal injection, and oral administration .…”

Efficient extraction of cucurbitacins from Diplocyclos palmatus (L.) C. Jeffrey: Optimization using response surface methodology, extraction methods and study of some important bioactivities

“…The HPLC apparatus was equipped with quaternary pump, autosampler, and UV detector (Jasco, Japan). The separation of cucurbitacins was achieved on Hiber C18 column (250x4.6 mm, 5 μm) and using published protocol with minor modifications 48 . The mobile phase with solvents acetonitrile, water and methanol (32:35:33, v/v/v) was used.…”

Study on the Metabonomics Mechanism of Mongolian Medical Andai Therapy on Healthy People

“…Compared with the content in the experimental group, more metabolites found in the control group metabolites are mostly intermediate metabolites of various biochemical reactions, such as 2-hydroxy-2-glutaric acid is the pentose phosphate intermediate [ 8 ], chlorinated acid cyclohexylamine is cyclohexylamine-generated intermediate [ 9 ], and l-methylinosine is the center of the cancer carbon metabolites [ 7 , 10 – 12 ]. If these products are not eliminated in time, there will be some harm to the human body.…”