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

Dermal absorption and excretion of MGK R11 [2,3:4,5-bis(2-butylene) te trahydro-2 furaldehyde, McLaughlin Gormley King Company, Minneapolis, MN] was studied using [C-14]MGK R11 either by itself or formulated wit h DEET (N,N-diethyl-m-toluamide), MGK 264 (N-octylbicycloheptene dicar boximide), and MGK 326 (di-n-propyl-isocinchomeronate). Each of these two formulations was tested on four young, healthy male volunteers, us ing a single topical application on the forearm under nonocclusive con ditions for an 8 h period. Blood from the ipsilateral and contralatera l arms, urine, and feces were collected at selected intervals during t he 8 h application and through a 120 h postapplication period. The app lication area was also tape-stripped to determine if any of the test m aterial accumulated in the stratum corneum. These samples provided dat a that permitted some insight into the kinetics of penetration and eli mination processes of MGK R11. Urine samples, swabs, and skin rinse sa mples were analyzed by high-performance liquid chromatography (HPLC) t o characterize the metabolic profile, identify the major metabolites, and determine the metabolic pathway. MGK R11, either by itself or form ulated, was poorly absorbed through the skin as shown by the amount of radioactivity excreted in the urine and the very low plasma radioacti vity level in the ipsilateral plasma. When dosed by itself, approximat ely 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% o f the dose was excreted in the feces. There was no evidence of accumul ation of MGK R11 in the skin, as evidenced by low amounts of radioacti vity in the tape strippings. A significant portion of the dosed radioa ctivity was recovered from the dome covering the dosing site amounting to 67% of the compound by itself or 27% of the formulated product, in dicating a difference of volatility depending on the formulation. The rest of the external radioactivity was present in the swabs. Total rec overy of the applied radioactivity was 89.9% and 99.5% for MGK R11 and the formulated product, respectively. Radiochemical analyses of the s wab composites indicated a 30% degradation of parent compound in the o ne-component swabs and no degradation in the four-component swabs. Abs orbed MGK; R11 was completely metabolized prior to its excretion in th e urine to two metabolites that accounted for 95% of the urinary metab olites. The major metabolic pathway is by oxidation of the aldehyde to the corresponding acid or reduction of the aldehyde to the correspond ing alcohol followed by conjugation to produce the glucuronide.