DERMAL ABSORPTION AND MASS-BALANCE OF MGK-326 AND REFORMULATED MGK-326 IN HUMAN VOLUNTEERS

Dermal absorption and excretion of MGK 326 (di-n-propylisocinchomerona te, McLaughlin Gormley King Company, Minneapolis, MN) was studied usin g [C-14]MGK 326, either by itself or formulated with DEET (N,N-diethyl -m-toluamide) and MGK 264 (N-octylbicycloheptene dicarboximide). Each of these two formulations was tested on four young, healthy male volun teers, using a single topical application on the forearm under nonoccl usive conditions for 8 hr. Blood from the ipsilateral and contralatera l arms, urine, and feces were collected at intervals during the 8 hr a pplication and 120 hr post-application periods. The application area w as also tape-stripped to determine if any of the test material accumul ated in the stratum corneum. These samples provided data that permitte d some insight into the kinetics of penetration and elimination proces ses of MGK 326. A significant difference was observed between the abso rption rate of MGK 326 alone and MGK 326 formulated with DEET and MGK 264. When dosed by itself, approximately 25% of the MGK 326 was absorb ed through the skin at a relatively rapid rate. In contrast, only simi lar to 3% of the formulated MGK 326 was absorbed and the absorption oc curred at a slower rate. Radioactivity levels in plasma taken from the contralateral arm were similar to 10-13% of that from the ipsilateral arm during the period of contact. The absorbed radioactivity levels d ecreased rapidly during the postcontact period. The time required for 50% reduction in radioactivity (t 1/2) in ipsilateral plasma samples a fter peak concentration was calculated to be 1.13 hr for MGK 326 alone and 1.35 hr for the formulated compound. This was independent of the absorption rate. There was no evidence of accumulation of MGK 326 in t he skin. Elimination appeared to be primarily through the kidneys. The results clearly show that the rate and extent of absorption of MGK 32 6 through human skin are highly dependent upon how it is formulated. T he rate of elimination is independent of the formulation. This study h ighlights the importance of the formulation in dermal penetration stud ies.