Erucylphosphocholine: pharmacokinetics, biodistribution and CNS-accumulation in the rat after intravenous administration

Abstract

The clinical use of alkylphosphocholines (APC) in cancer patients is restricted because of the high gastrointestinal toxicity and the need for oral administration. Therefore we evaluated the clinical pharmacology of erucylphosphocholine (ErPC), the first derivative of the APC family suitable for intravenous administration with strong antineoplastic activity, in vitro and in vivo in rats. The pharmacokinetic parameters after a single intravenous dose of 40 mg/kg were calculated using a two-compartment model: C(max) = 1.6 +/- 0.3 micromol/ml, T(1/2alpha) = 0.18 +/- 0.09 h, T(1/2beta) = 3.3 +/- 0.88 h, clearance = 9.7 +/- 1.2 ml/h, AUC = 2.5 +/- 0.3 micromol/ml per h and Vss = 40.4 +/- 7.9 ml. Biodistribution studies were performed after repeated ErPC administration at different doses. Intravenous injections of 20 mg/kg given at intervals of 48 h for up to 4 weeks were well tolerated. Neither clinical evaluation nor laboratory parameters (haematology and clinical chemistry) revealed toxic side effects. In contrast, higher doses of ErPC (40 mg/kg per 48 h) led to weight loss. After 2 and 4 weeks of therapy with 20 mg/kg per 48 h a high ErPC accumulation was found in the adrenal glands, small intestine and brain. The brain to serum concentration ratios averaged 2.1 after 2 weeks and 4.5 after 4 weeks. Significant leucocytosis and thrombocytosis were observed after 4 weeks of ErPC treatment. The findings suggest that ErPC is a suitable candidate for clinical trials. In particular, owing to the high accumulation in brain tissue, ErPC is a potential agent for chemotherapy against malignant brain tumours.

The Translocator Protein Radioligand 18F-DPA-714 Monitors Antitumor Effect of Erufosine in a Rat 9L Intracranial Glioma Model

“…They noted a positive treatment response, but only in subcutaneous tumors, whereas the intracerebral tumors showed a poor response to therapy, which they explained by a limited access of ErPC to the central nervous system leading to low concentrations of the drug in the intracranial tumors. However, other studies reported drug concentrations higher than 200 nmol/g in rat and mouse brain tissue on ErPC and ErPC3 administration at 40 mg/kg (19,20), concentrations exceeding the threshold doses of ErPC (lethal concentration 50 [LC50; concentration required to kill 50% of a population 5 29-70 mM (17)) and ErPC3 (LC50 , 50 mM, this study) that induce cytotoxicity in glioma cell lines in vitro, suggesting that the concentration of ErPC3 reaching the intracranial 9L tumors is sufficient to induce tumor cell death.…”

“…ErPC demonstrated antitumor activity in several human and rat glioma cell lines (17,18) and induced apoptosis in the chemoresistant glioblastoma cell lines (15). Erucylphosphohomocholine (ErPC3; Erufosine [Genzyme]) is a congener of ErPC with higher water solubility and is able to cross the blood-brain barrier (19,20). Similarly to ErPC, ErPC3 exhibits potent antitumor activities in the micromolar range (21) and induces apoptosis in otherwise highly apoptosis-resistant glioblastoma cell lines (15).…”

Alkylphosphocholine-induced glioma cell death is BCL-XL-sensitive, caspase-independent and characterized by massive cytoplasmic vacuole formation

“…10 Also, APC have no intense substrate affinity for phospholipid-metabolizing enzymes, which increases their half-life and may allow accumulation in tumor cells. 11 Finally, the accumulation of APC in brain 12 provides an additional rationale to assess such agents in the experimental treatment of gliomas. Here, we characterize the cytotoxic effects of two APC compounds ((S)-1-O-phosphocholin-2-O-acetyl-octadecane (SOC-2)) 13 and (rac)-1-O-phosphocholin-2-O-methyl-octadecane (racOMe)), patent pending) in a panel of human malignant glioma cell lines.…”

Interaction of Alkylphospholipid Formulations with Breast Cancer Cells in the Context of Anticancer Drug Development

“…1), significant differences were found in pharmacological properties. This structural modification increases hydrophobicity resulting in the formation of lamellar supramolecular structures, which abolished hemolytic side effects and allows Erucylphosphocholine to be administrated intravenously (Erdlenbruch et al, 1999;Kaufmann-Kolle et al, 1996;van Blitterswijk & Verheij, 2008). It is a potent inducer of apoptosis (Jendrossek et al, 2003) that exerts more potent antineoplastic effects in vitro and in vivo than Miltefosine.…”