Impact of inflammation-mediated changes in expression and activity of PGP and CYP3A on drug disposition.

摘要

The aims of this work were to investigate the effects of acute inflammation on the intestinal expression of P-glycoprotein (PGP), a xenobiotic transporter, and cytochrome P450 3A (CYP3A), a metabolic enzyme, and the resultant alterations in the functional activity of these proteins. Changes in gene expression during inflammation were detected with RT-PCR. Ussing chamber-mounted intestinal tissues were used to study the transport and metabolism of compounds in the intestine. PGP-mediated efflux of digoxin was reduced in endotoxemia, mirroring the suppression in mdr1a mRNA expression. CYP3A-mediated metabolism of 7-benzyloxyquinoline was also suppressed in endotoxemia, confirming changes measured in CYP3A mRNA expression. We conclude that the intestine is an active participant in the acute phase response, and alterations in PGP and CYP3A expression and/or activity during inflammation may alter the oral bioavailability of drugs. These findings highlight a potential source of inter-individual variability in inflammatory disease, which may result in drug-disease interactions.