Venlafaxine induces P-glycoprotein in human Caco-2 cells

Purpose: The objective of this study was to evaluate the effect of a treatment with venlafaxine on the expression of multidrug resistance-associated protein (MRP) gene and multidrug resistance-related proteins (MDR) in human colon carcinoma cells (Caco-2) compared to a known P-glycoprotein (PGY1) inducer, rifampine. Methods: Caco-2 cells were treated with venlafaxine (50 μM, 100 μM, 250 μM, and 500 μM) and rifampin (25 μM and 50 μM) to test the possible induction of MRP and MDR expression. The treatment times used were 1.5, 3, 6, 12, 24, 48, and 72 h. RNA was isolated from the cells, and MDR and MRP genes were amplified using PCR. Results: Both venlafaxine and rifampine had the most dramatic effect at the 50 μM concentration. There was an increase in MDR and MRP expression in Caco-2 cells after the acute treatment (1.5, 3, and 6 h) with venlafaxine. These results were similar to those with rifampine. Conclusions: PGY1 contributes to renal and biliary elimination of drugs by transporting the drug out of the cell and back into the intestinal lumen, where drugs may be further metabolized by intestinal enzymes such as Cytochrome P (CYP)-450 3A4. Its function is to limit the bioavailability of orally administered compounds. Due to the increase in MDR and MRP gene expression seen after the acute treatment with venlafaxine, there could be a potential drug-drug interaction with other medications that are metabolized via CYP450-3A4 when coadministered with venlafaxine.