Stereoselective Permeation of Tretinoin and Isotretinoin through Enhancer-Treated Rat Skin. II. Effects of Lipophilic Penetration Enhnacers

Many properties of chemicals depend on their stereochemistry. Among these, the effects of stereoisomerism on percutaneous absorption of drugs are not well studied. We have previously shown that permeation of tretinoin and isotretinoin (two geometric isomers) through hydrophilic enhancers-treated rat skin is stereoselective. As, depending on their lipophilicity, penetration enhancers can change permeation pathway of drugs, it was decided here to investigate permeation of the same stereoisomers through lipophilic enhancer-treated skin.

Oleic acid, that mainly affects stratum corneum intercellular lipids, was chosen as the lipophilic penetration enhancer for this study. Permeation of retinoids through untreated and enhancer-treated rat skin was studied at room temperature. These studies employed static diffusion cells, saturated drugs in propylene glycol:water mixture (75:25, v/v) as the donor phase and aqueous solution of Tween₂₀ as the receptor phase.

Permeation of retinoids through untreated skin was too low to be detected in the receptor phase even by the used HPLC method with sensitivity of 10 ng ml^-1. Oleic acid increased the permabilities of retinoids to measurable values. In oleic acid-treated skin, tretinoin permeated by about 1.3 times faster than isotretinoin (P<0.0001). However, permeability coefficients, that are concentration-normalized fluxes, showed a reverse order. Permeability coefficient of isotretinoin through the same membrane was significantly (P=0.0002) higher than that of tretinoin. On the other hand, the difference between permeation lag-times of retinoids was not that significant (P=0.062). These data show that stereoselctive permeation of these retinoids through oleic acid- treated rat skin is mainly a partitioning-related phenomenon. Diffusion co efficient might play only a minor role.

Present results are partly different from those of our previous study on hydrophilic enhancers and clearly show that the type of enhancer and its mode of action can affect stereoselective permeation of drugs through the skin.