Toxicokinetics and metabolism of N-[(14)C]N-methyl-2-pyrrolidone in male Sprague-Dawley rats: in vivo and in vitro percutaneous absorption.

Abstract

Neat N-methyl-2-pyrrolidone (NMP) rapidly penetrated into the skin of male Sprague-Dawley rats after in vivo and in vitro topical application. At the two topical doses tested in vivo, no steady state was observed. The maximal absorption fluxes were 10 and 20 mg/cm(2)/h for 20 microl/cm(2) and 40 microl/cm(2), respectively. Similar results were observed after in vitro topical application of neat [(14)C]NMP (25-400 microl/cm(2)) in fresh full-thickness skin. Whatever the dose tested, the percutaneous absorption fluxes increased with exposure time to reach a maximum value (F(max)) and then decreased. F(max) and the time to reach it (T(max)) increased as the dose increased. At the highest dose, which may be considered as an "infinite dose," the maximal flux (7.7 +/- 1.1 mg/cm(2)/h, n = 12) occurred 6 h after the topical application of NMP. The decrease on percutaneous absorption flux was correlated with the dilution of neat NMP with water from the receptor fluid. A semi-quantitative mathematical model was developed to describe the absorption flux of NMP taking into account the transfer of water through the skin. The K(p) values determined from the different aqueous solutions of NMP (1:1 to 1:32, v/v) were not significantly different. The mean value was 6.4 (10(-3) cm/h) (range, 4.7 to 7.6). Occlusion did not affect the percutaneous absorption flux of neat NMP. Desquamation increased the percutaneous absorption of NMP slightly. The skin did not metabolize NMP. The flux was dependent on the thickness of the skin and was proportional to the concentration of NMP. These findings suggest a passive diffusion of NMP through the skin.