ANALYSIS OF IN-VITRO RAT SKIN PERMEATION AND METABOLISM OF SM-10902, PRODRUG OF SYNTHETIC PROSTACYCLIN ANALOG

The permeation and metabolism of SM-10902, a prodrug of a synthetic pr ostacyclin analogue (SM-10906), in the rat skin were studied using a f low through type diffusion cell and were compared with those of SM-109 06. Absorbed SM-10902 was entirely metabolized to the bioactive form, SM-10906, in the rat skin. The appearance of SM-10906 to the receptor was faster when applied as SM-10902 than when applied as SM-10906 in b oth types of intact and stripped skin. From the analysis of these perm eation profiles by the two-layer skin model with a metabolic pathway, the diffusion constants of SM-10902 in the stratum corneum and the low er layer were 70 and 6 times of those of SM-10906, respectively. On th e other hand, the partition coefficient of SM-10902 from the ointment to the stratum corneum and the lower layer were equal to and twice as high as those of SM-10906, respectively. Furthermore, to clarify the s uitable characteristic for skin permeation, the relationship between t he metabolic rate in the lower layer and the permeation profile of the ester prodrug was estimated by computer simulation. The appearance of metabolite to the receptor increases with the increase of metabolic r ate and reaches a maximum point and thereafter decreases to a plateau level. According to this simulation, it is shown that SM-10902 has a f avorable characteristic from the view point of metabolic rate.