ENHANCING EFFECT OF N-DODECYL-2-PYRROLIDONE ON THE PERCUTANEOUS-ABSORPTION OF 5-FLUOROURACIL DERIVATIVES

The enhancing effects of N-dodecyl-2-pyrrolidone (NDP) on the percutan eous absorption of doxifluridine (DOX), 5-fluorouracil (5-FU), tegafur (TEG) and carmofur (CAR) were examined using an in vitro penetration technique and rat skin. Phosphate buffered isotonic saline (PBS), prop ylene glycol (PG) and PG containing 0.4 NDP (PGNDP) were applied as th e donor solution. The correlation between the n-octanol/water partitio n coefficients and the permeability coefficients of DOX, 5-FU and TEG was investigated using both logarithmic plots. It was determined that the permeability coefficients are significantly correlated with their n-octanol/water partition coefficients on PBS. This result suggested t hat the non-polar stratum corneum lipid lamella in the skin might act as a rate limiting step on the skin penetration of DOX, 5-FU and TEG. The permeability coefficient of DOX, 5-FU and TEG was increased on PGN DP. The enhancing effect of NDP on the permeability coefficient was mo re effective at higher hydrophilic drugs, the values of the permeabili ty coefficient had almost the same values on PGNDP and the dependency of the permeability coefficient on the n-octanol/water partition coeff icient disappeared in the presence of NDP. These results indicated tha t the enhancing effect of NDP on the percutaneous absorption of DOX, 5 -FU and TEG might he closely related to the perturbation of stratum co rneum lipid lamella. Since it has been well recognized that CAR is dec omposed into 5-FU in neutral and alkaline solution, the decomposition rate of CAR was measured using PBS solution and was found to be very r apid (K-d = 3.17 h(-1), t(1/2) = 13.1 min). The total concentrations o f CAR plus 5-FU in the acceptor compartment were used to determine the permeability coefficient of CAR. The obtained value of the permeabili ty coefficient of CAR on PG was almost the same as that of TEG on PG ( CAR: 1.11 x 10(-3) cm/h, TEG: 1.24 x 10(-3) cm/h), while that of CAR o n PGNDP was smaller than that of TEG on PGNDP (CAR: 6.06 x 10(-3) cm/h , TEG: 1.24 x 10(-2) cm/h). To determine the lipophilic property of CA R, the lipophilic index (log k') was measured by HPLC. The value of th e lipophilic index of CAR was 92 times higher than that of TEG. These results indicated that CAR is a higher lipophilic compound, and the sm aller value of the permeability coefficient of CAR compared with that of TEG on PGNDP might be caused by the strong binding of CAR to the ra t skin (dermis). The dermis might act as a rate limiting step on the s kin penetration of CAR, and the percutaneous absorption of CAR might b e controlled by both the stratum corneum and the dermis.