Cytotoxicity of sulfadiazine (SDZ) complexed with PAMAM dendrimers of fourth generation (SDZ-DG4) determined by MTT assay and LDH leakage, was reduced on covered (with mucins) but not on nude (without mucins) Caco-2 cell line. SDZ-DG4 adsorption and uptake on nude and covered Caco-2 cells, determined by flow cytometry and fluorescence confocal microscopy indicated that positively charged DG4 remained electrostatically attracted to the negatively charged mucins macromolecules. Hence, the in vivo accession of cationic dendrimers to epithelial cells could partly be impaired by their entrapment into mucins. This fact could account for an in vivo decreased cytotoxicity. Besides this finding, when orally administered to Wistar rats, no differences in SDZ biodistribution were found between SDZ-DG4 and free SDZ. However, when intravenously administered at 1.5 mg SDZ per kg body weight, Cmax for free SDZ was 0.7+/-0.2 microg vs. 2.7+/-0.4 microg/ml for SDZ-DG4, whereas AUC0-3 for free SDZ was 0.8+/-0.6 microg/h ml vs. 5.2+/-2 microg/h ml for SDZ-DG4. SDZ-DG4 initial volume distribution (Vd) was 2.6-fold lower than for free SDZ. Remarkably, 3 h upon SDZ-DG4 administration, SDZ concentration in muscle and in brain were 17- and 10-fold higher, respectively, than those achieved with free SDZ.