Pharmacokinetics of the thioether phospholipid analogue BM 41.440 in rats

Abstract

BM 41.440 (1-hexadecylmercapto-2-methoxymethyl-rac-glycero-3-phosphocholine) is a cytotoxic thioether phospholipid analogue that recently has entered phase I trials in cancer patients. The objective of this study was to evaluate the pharmacokinetics of this compound in female rats after administration of a single oral dose (15 mg/kg body weight [bw] ). Furthermore, BM 41.440 serum concentrations were determined under a daily oral treatment of up to 13 weeks. Blood samples were obtained via permanent catheters from the femoral arteries before and after drug administration for a total of 120 hr. Urine was collected in 24 hr-intervals for 120 hr; the volume was measured, and aliquots were stored at -20 C until analytical determination of the thioether derivative. BM 41.440 was assayed in serum and urine by means of a specific, newly developed reverse-phase high pressure liquid chromatography technique. Mean maximum serum concentrations (1.7 micrograms/ml, n = 4 animals) were attained after seven hr. A terminal half-life of ca. 27 hr was calculated from the rate constant for the terminal elimination phase (lambda z approximately 0.026/hr). The mean serum BM 41.440 concentration-time-area-under-the-curve was 52.9 mg X hr/l. The ratio of total body clearance to absorption fraction was 4.7 ml/min X kg bw. Only a small amount of the drug was found in the urine. The quantity excreted in the urine during a 24 hr-interval never exceeded 1.5% of the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)

ET-18-OCH3 (Edelfosine): A Selective Antitumour Lipid Targeting Apoptosis Through Intracellular Activation of Fas / CD95 Death Receptor

“…This selectivity of ET-18-OCH 3 in achieving an apoptotic response in tumour cells, sparing normal cells, is an outstanding hallmark in its antitumour action. However, not all tumour cells are sensitive to ET-18-OCH 3 , and a number of cancer cells, such as the chronic myelogenous leukemia K562 and the T lymphoid leukemia HPB-ALL, show resistance to the ET-18-OCH 3 action [30,47]. Structurally related analogues of ET-18-OCH 3 that show similar physicochemical properties lack proapoptotic activity [15].…”

“…Increasing amounts of serum inhibit the cytotoxic effects of ET-18-OCH 3 in a concentration-dependent manner [50][51][52](Gajate, C. and Mollinedo, F., unpublished data). The specific action of ET-18-OCH 3 and other ATLs on apoptosis should be separated from their non-specific lytic effect on membranes (detergent-like action) shown by ATLs at elevated doses. When used at high concentrations, ATLs act as membrane-active detergent molecules disrupting the orderly bilayer structure of the plasma membrane and forming micellar clusters, which give rise to pores and holes in cell membranes [53,54].…”

“…: (+34)-923 294806; Fax: (+34)-923 294795; E-mail: fmollin@usal.es remarkable features of AEPs and APCs are their low metabolism rates in vitro and in vivo, and the fact that they do not target the DNA, but act at the cell membrane. Although the first ATLs were synthesized in the late 60s as metabolically stable analogues of lysophosphocholine [14], the finding in 1997 of the selective apoptosis in tumour cells treated with the ATL prototype ET-18-OCH 3 [15] has rekindled interest in these compounds, and especially in ET-18-OCH 3 as a promising and selective antitumour drug. Apoptosis or cell suicide is an intrinsic cell death programme that occurs in various physiological and pathological situations [16][17][18].…”

“…This represents a novel and unique mechanism of action in cancer chemotherapy. The present review covers the state of the art in the underlying mechanisms of the antitumour effect of ET-18-OCH 3 , emphasising the effect of ET-18-OCH 3 in triggering apoptosis in tumour cells through activation of the apoptotic machinery that was dormant in cancer cells. We also propose a tentative molecular model for the intracellular activation of the Fas/CD95 death receptor by ET-18-OCH 3 as a novel way to target cancer cells.…”

“…1). Additional AEP and APC analogues have been synthesized that show promising antitumour activities, including 1-hexadecylthio-2-methoxymethyl-racglycero-3-phosphocholine (BM 41.440, ilmofosine) [2][3][4][5], the cyclic analogue SRI 62-834 [6], octadecyl-(N,Ndimethyl-piperidinio-4-yl)-phosphate (D-21266, perifosine) [7][8][9] and erucylphosphocholine [10][11][12][13] (Fig. 1).…”