Intestinal disposition of farnesol in the rat ileum.

B110 Introduction: Farnesol (FOH) is a dietary isoprenoid compound found in lemongrass and tea that has demonstrated promising in vivo activity in the azoxymethane-aberrant crypt foci model of colon cancer in Fischer 344 (F344) rats. The apparent mechanism of activity for FOH may involve regulation of the cholesterol biosynthesis pathway with respect to protein isoprenylation, an essential process for the activation of oncogenic Ras. The pharmacokinetics and intestinal disposition of FOH, however, have not been fully described. Methods: The intestinal disposition of FOH was investigated in male Sprague-Dawley (SD) and F344 rats using the single-pass intestinal perfusion method with mesenteric vein sampling. A 20 uM solution of trans-, trans-FOH and trans-, trans-[3-14C]-FOH (activity of 0.2 uCi/mL) in buffer (pH = 6.5) was perfused through a 10 - 15 cm segment of the ileum over a period of 40 - 60 minutes. Outlet perfusate and mesenteric blood samples were collected every 5 minutes during the perfusion. Perfusate and plasma samples were analyzed by liquid scintillation counting for permeability determination and radiometric HPLC for the presence of parent and/or metabolites. Results: In both the SD and F344 strains, [14C]-FOH was the sole radiolabelled compound detected in the outlet perfusate. Permeability values of 3.11 x 10-5 and 4.19 x 10-5 cm/sec from perfusate were determined for SD and F344 rats, respectively, whereas influx of parent compound in blood was only 1.82 x 10-5 and 8.00 x 10-6 cm/sec (SD and F344 rats, respectively). In the mesenteric plasma of both strains, [14C]-FOH and [14C]-FOH-associated metabolites were detected. Furthermore, one [14C]-FOH-associated metabolite, of slightly higher polarity than [14C]-FOH, accounted for the majority of the radioactivity detected in the mesenteric plasma of both strains. Conclusions: Permeability values from perfusate indicates that FOH is a highly permeable compound, however, low influx of parent compound in blood and rapid conversion to polar derivates suggest that FOH is substantially metabolized in the enterocyte during transport from the lumen. This extensive intestinal first pass metabolism of FOH may have implications in the cancer prevention activity of this compound, particularly for cancers of the gastrointestinal tract. Further delineation of the intestinal disposition and pharmacokinetics of FOH should provide a basis for designing optimal dosing strategies. Acknowledgement: Financial support from McKesson Bioservices through NCI subcontract N02-CN-95016