The gastrointestinal absorption of paraquat (1,1'-dimethyl-4,4'-bipyridylium) was studied using the isolated mucosa from different regions of the gastrointestinal tract of rats. Tissues were stripped of their muscle layers and the viability of the mucosa was maintained in flux chambers by bathing both serosal and luminal membranes with separate oxygenated solutions. Paraquat absorption, transmucosal potential difference (PD), and permeability of the mucosa were studied. Exposure of the luminal side of isolated mucosae to paraquat (100 mg/ml) resulted in greater paraquat absorption across the small intestine compared to other regions of the gastrointestinal tract. The descending order of tissue absorption (as %/cm2 mucosa) was jejunum (17.6 +/- 0.8%), ileum (10 +/- 2.7%), colon (5.7 +/- 3.2%), duodenum (5.5 +/- 1.3%), stomach (2 +/- 0.8%), and esophagus (0.5 +/- 0.7%). Mucosal uptake of paraquat in the ileum was nonlinear over a luminal concentration range 2-200 mg/ml. Three phases to paraquat absorption were identified in this region of the small intestine: (i) a rate which was faster than diffusion (2-20 mg/ml paraquat); (ii) a rate which was slower than diffusion and obeyed saturation kinetics, with an apparent Km = 116 mM and Vmax = 11.3 mumol/g/hr, at paraquat concentrations up to 150 mg/ml: and (iii) a rate similar to that of diffusion at 200 mg/ml paraquat. Paraquat absorption at 200 mg/ml was also associated with an increase in mucosal permeability and reduction in PD. Inhibition of tissue metabolism resulted in a linear or diffusional paraquat absorption over a wide luminal concentration range (2-200 mg/ml). It is suggested, therefore, that paraquat absorption in the rat occurs principally in the small intestine and by a mechanism which consists of facilitated, saturable, and diffusional components. Knowledge of the mechanism by which paraquat gains entry to the bloodstream may offer new approaches to the development of safer formulations of the herbicide.