Brain and muscle of Wistar rats are the main targets of intravenous dendrimeric sulfadiazine

M.J. PRIETO, P. SCHILRREFF, M.V. DEFAIN TESORIERO, M.J. MORILLA, E.L. ROMERO

INTERNATIONAL JOURNAL OF PHARMACEUTICS

ELSEVIER SCIENCE BV

Año: 2008 vol. 360 p. 204 - 212

0378-5173

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 onnude (without mucins) Caco-2 cell line. SDZ–DG4 adsorption and uptake on nude and covered Caco-2 cells, determined by flowcytometry 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 1.5mg SDZ per kg bodyweight, Cmax for free SDZwas 0.7±0.2g/ml vs. 2.7±0.4g/ml for SDZ–DG4, whereas AUC0−3 for free SDZwas 0.8±0.6g/h ml vs. 5.2±2g/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.