Deacylation-reacylation cycle: a possible absorption mechanism for the novel lymphotropic antitumor agent dipalmitoylphosphatidylfluorouridine in rats.
Dipalmitoylphosphatidylfluorouridine (DPPF) is a potent antitumor agent that selectively gains access to the lymphatic system. To determine whether DPPF enters the lymph in an unmodified form, we administered DPPF orally to rats and analyzed lymph collected from a cannula in the thoracic duct. Although lymph was found to contain only very low levels of DPPF, two congeners of DPPF were detected at high levels. Instrumental analysis demonstrated that these congeners are 1-palmitoyl-2-arachidonoylphosphatidylfluorouridine (PAPF) and 1-palmitoyl-2-linoleoyl-phosphatidylfluorouridine (PLPF). PAPF and PLPF levels in thoracic lymph were shown to be approximately 30 times higher than those in plasma. These results suggest that DPPF is absorbed from the intestinal tract via the deacylation-reacylation cycle for the uptake of phospholipids and is selectively delivered to the lymphatic route after oral administration. DPPF is a candidate drug for the treatment of tumor metastasis, especially in cases where metastasis has occurred via the lymphatic route.
Sakai
A
A
Institute for Life Science Research, Asahi Chemical Industry Corporation, Ltd., Shizuoka, Japan.
Mori
N
N
Shuto
S
S
Suzuki
T
T
D000215:Acylation; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D020404:Glycerophospholipids; D007408:Intestinal Absorption; D008196:Lymph / Q000378:metabolism*; D008208:Lymphatic System / Q000378:metabolism; D008297:Male; D010712:Phosphatidic Acids / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013897:Thoracic Duct / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D020404:Glycerophospholipids; D010712:Phosphatidic Acids; C082139:1,2-dipalmitoylphosphatidylfluorouridine; C082140:1-palmitoyl-2-arachidonoylphosphatidylfluorouridine; C082141:1-palmitoyl-2-linoleoylphosphatidylfluorouridine; D014529:Uridine