Cytokines influence mRNA expression of cytochrome P450 3A4 and MDRI in intestinal cells

Inflammation and infection may have the potential to increase the bioavaila bility of drugs. This effect could be because of a reduced metabolism of xe nobiotics in the liver and/or the intestines, or because of alterations in small intestinal permeability, mucosal flow, and expression of drug efflux transporters such as glycoprotein (Pgp). To assess the impact on intestinal epithelium of some proinflammatory cytokines and macrophages on permeabili ty and mRNA expression of CYP3A4 and MDRI (multidrug resistance, coding for Pgp), we used the Caco-8 cell line os a model. Exposure to proinflammatory cytokines and macrophages decreased the mRNA expression of CYP3A4 and incr eased the expression of MDR1 mRNA in the Caco-2 cells. In parallel, the cel l layer permeability, as measured by sodium fluorescein flux, increased for all cytokine and macrophage treatments, whereas the effect on transepithel ial electrical resistance (TEER) varied. Our findings suggest that inflamma tion and infection trigger several different cellular responses that may af fect drug bioavailability; that is hampered CYP3A4 expression, increased pe rmeability of the epithelial cell layer, and enhanced Pgp-mediated countera ctive transport. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:638-646. 2001.