Absorption and Mass Balance of Mgk R11 and Mgk R11 Formulated with Deet, Mgk 264, and Mgk 326 Following an 8 Hour Dermal Exposure in Human Volunteers

Abstract

Dermal absorption and excretion of MGK R11 [2,3:4,5-bis(2-butylene) tetrahydro-2 furaldehyde, McLaughlin Gormley King Company, Minneapolis, MN] was studied using [¹⁴C]MGK R11 either by itself or formulated with DEET (N,N-diethyl-m-toluamide), MGK 264 (N-octylbicycloheptene dicarboximide), and MGK 326 (di-n-propyl-isocinchomeronate). 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 an 8 h period. Blood from the ipsilateral and contralateral arms, urine, and feces were collected at selected intervals during the 8 h application and through a 120 h postapplication period. 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 R11. Urine samples, swabs, and skin rinse samples were analyzed by high-performance liquid chromatography (HPLC) to characterize the metabolic profile, identify the major metabolites, and determine the metabolic pathway.

MGK R11, either by itself or formulated, was poorly absorbed through the skin as shown by the amount of radioactivity excreted in the urine and the very low plasma radioactivity level in the ipsilateral plasma. When dosed by itself, approximately 8% of the dose was excreted in the urine. In contrast, only 3% of the formulated MGK R11 was excreted in the urine. Approximately 0.3% of the dose was excreted in the feces. There was no evidence of accumulation of MGK R11 in the skin, as evidenced by low amounts of radioactivity in the tape strippings. A significant portion of the dosed radioactivity was recovered from the dome covering the dosing site amounting to 67% of the compound by itself or 27% of the formulated product, indicating a difference of volatility depending on the formulation. The rest of the external radioactivity was present in the swabs. Total recovery of the applied radioactivity was 89.9% and 99.5% for MGK R11 and the formulated product, respectively. Radiochemical analyses of the swab composites indicated a 30% degradation of parent compound in the one-component swabs and no degradation in the four-component swabs. Absorbed MGK R11 was completely metabolized prior to its excretion in the urine to two metabolites that accounted for 95% of the urinary metabolites. The major metabolic pathway is by oxidation of the aldehyde to the corresponding acid or reduction of the aldehyde to the corresponding alcohol followed by conjugation to produce the glucuronide.