Enhancing Effect of N-Dodecyl-2-pyrrolidone on the Parcutaneous Absorption of 5-Fluorouracil Derivatives

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The enhancing effects of N-dodecyl-2-pyrrolidone (NDP) on the percutaneous absorption of doxifluoridine (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), propylene glycol (PG) and PG containing 0.4 M NDP (PGNDP) were applied as the donor solution. The correlation between the n-octanol/water partition coefficients and the permeability coefficient 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 that 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 PGNDP. The enhancing effect of NDP on the permeability coefficient was more effective at higher hydrophilic drugs, the values of the permeability coefficient had almost the same values on PGNDP and the dependency of the permeability coefficient on the n-octanol/water partition coefficient disappeared in the presence of NDP. These results indicated that the enhancing effect of NDP on the percutaneous absorption of DOX, 5-FU and TEG might be closely related to the perturbation of stratum corneum lipid lamella. Since in has been well recognized that CAR is decomposed into 5-FU in neutral and alkaline solution, the decomposition rate of CAR was measured using PBS solution and was found to be very rapid (K_d=3.17 h^<-1>, t_<1/2>13.1 min). The total concentrations of CAR plus 5-FU in the acceptor compartment were used to determine the permeability coefficient of CAR. The obtained value of the permeability coefficient of CAR on PG was almost the same as that of TEG on PG (CAR : 1.11×10^<-3> cm/h, TEG : 1.24×10^<-3> cm/h), while that of CAR on PGNDP was smaller than that of TEG on PGNDP (CAR : 6.06×10^<-3> cm/h, TEG : 1.24×10^<-2> cm/h). To determine the lipophilic property of CAR, the lipophilic index (log k') was measured by HPLC. The value of the lipophilic index of CAR was 92 times higher than that of TEG. These results indicated that CAR is a higher lipophilic compound, and the smaller 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 rat skin (dermis). The dermis might act as a rate limiting step on the skin penetration of CAR, and the percutaneous absorption of CAR might be controlled by both the stratum corneum and the dermis.
公益社団法人日本薬学会の論文
1998-05-15

Enhancing Effect of N-Dodecyl-2-pyrrolidone on the Parcutaneous Absorption of 5-Fluorouracil Derivatives

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