Hydrolysis of 3', 5'-Dioctanoyl-5-fluoro-2'-deoxyuridine (FdUrd-C8) in Rabbit and Human Plasma and Its Release from Oily Solution

抄録

Hydrolysis of 3', 5'-dioctanoyl-5-fluoro-2'-deoxyuridine (FdUrd-C8), a lipophilic prodrug of 5-fluoro-2'-deoxyuridine (FdUrd), 3'-octanoyl-5-fluoro-2'-deoxyuridine (3'-octanoyl FdUrd) and 5'-octanoyl-5-fluoro-2'-deoxyuridine (5'-octanoyl FdUrd) in the rabbit and human plasma and release of FdUrd-C8 and its hydrolyzed species from Lipiodol Ultra-Fluid (Lipiodol), an oily lymphographic agent, containing FdUrd-C8 were examined. The rates of hydrolysis of FdUrd-C8, 3'-octanoyl FdUrd and 5'-octanoyl FdUrd in the rabbit plasma were fast and almost the same among the three compounds ; half lives were 2.4, 3.6 and 3.9 min for 5'-octanoyl FdUrd, FdUrd-C8 and 3'-octanoyl FdUrd, respectively. In the human plasma, however, the rates of hydrolysis were much different among the three compounds and were slower than those in the rabbit plasma ; half lives were 11.5, 130 and 1020 min for 5'-octanoyl FdUrd, FdUrd-C8 and 3'-octanoyl FdUrd, respectively. Ratios of the rate constant of 5'-octanoyl FdUrd to that of 3'-octanoyl FdUrd were 1.6 and 85.7 in the rabbit plasma and in the human plasma, respectively. In a release study, although detected species in a release medium were different between the rabbit plasma and the human plasma and the amount of each species reflected the characteristics of esterase in each plasma, the total amounts of compounds released were almost the same both in the rabbit plasma and the human plasma. The existence of bovine serum albumin in a release medium increased the amount of compounds released from a Lipiodol solution to a greater extent than the existence of porcine liver esterase in the release medium. The FdUrd-C8 content in Lipiodol affected the duration of release but not the amount of compounds released.