Dermal Absorption and Mass Balance of MGK 326 and Reformulated MGK 326 in Human Volunteers

Abstract

Dermal absorption and excretion of MGK 326 (di-n-propyl-isocinchomeronate, McLaughlin Gormley King Company, Minneapolis, MN) was studied using [14C]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 volunteers, using a single topical application on the forearm under nonocclusive conditions for 8 hr. Blood from the ipsilateral and contralateral arms, urine, and feces were collected at intervals during the 8 hr application and 120 hr post-application periods. The application area was also tape-stripped to determine if any of the test material accumulated in the stratum corneum. These samples provided data that permitted some insight into the kinetics of penetration and elimination processes of MGK 326.A significant difference was observed between the absorption 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 absorbed through the skin at a relatively rapid rate. In contrast, only ∼ 3% of the formulated MGK 326 was absorbed and the absorption occurred at a slower rate. Radioactivity levels in plasma taken from the contralateral arm were ∼ 10–13% of that from the ipsilateral arm during the period of contact. The absorbed radioactivity levels decreased rapidly during the postcontact period. The time required for 50% reduction in radioactivity (t 1/2) in ipsilateral plasma samples after 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 the skin. Elimination appeared to be primarily through the kidneys.The results clearly show that the rate and extent of absorption of MGK 326 through human skin are highly dependent upon how it is formulated. The rate of elimination is independent of the formulation. This study highlights the importance of the formulation in dermal penetration studies.