To develop a more efficient transdermal delivery system, it is very important to regulate the intradermal disposition of drugs after topical application. We tried to elucidate the factors determining the intradermal disposition kinetics, especially drug penetration from the viable skin to the muscular layer, mainly based on the six-compartment model, including the contralateral skin and muscle for ten model drugs with different physicochemical characteristics. In vivo transdermal absorption study was performed for six model drugs using the stripped-skin rats. The fitting analyses by the six-compartment model gave the theoretical curves describing the observed data very well and the reasonable pharmacokinetic parameters, showing the pharmacokinetic model should be useful for the estimation of the intradermal disposition kinetics of drugs applied topically again. The simulation study using the pharmacokinetic parameters obtained above could show the relative contribution of the direct penetration and the distribution from the systemic circulation to the muscular distribution of drugs. The largest contribution of direct penetration was observed for antipyrine (90.8%) and the smallest was for felbinac (43.3%). Among the pharmacokinetic parameters obtained above, the clearance from the viable skin to the muscle (CL_vs–m) was found to be significantly correlated with the unbound fraction of drugs in the viable skin (fu_vs). Although the clearance from the viable skin to the plasma (CL_vs–p) also tended to increase as fu_vs increased, the ratio of CL_vs–m to CL_vs–p was significantly correlated with fu_vs, meaning that the larger amount of unbound drug in the viable skin significantly contributes to the direct penetration into the muscle more than to the systemic absorption. On the other hand, k_direct values obtained in in vitro penetration study—the penetration rate constant of drugs from the viable skin to the muscular layer—were found to be correlated with CL_vs–m values for seven model drugs. Therefore, adding the in vitro experiments for the other three model drugs, the multiple linear regression analysis of k_direct was performed for ten model drugs in terms of fu_vs, logarithm of the partition coefficient (Log P) and molecular weight. The results clearly showed the largest and significant contribution of fu_vs to the direct penetration of drugs from the viable skin to the muscular layer, indicating that a drug with the higher value of fu_vs in the viable skin can penetrate more into the muscular layer.