Venlafaxine induces P-glycoprotein in human Caco-2 cells

• Published in: Human psychopharmacology 2007-01, Vol.22 (1), p.49-53
• Main Authors: Ehret, M. J., Levin, G. M., Narasimhan, M., Rathinavelu, A.
• Format: Article
• Language: English
• Subjects: Antidepressive Agents, Second-Generation - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Caco-2 Cells; Cyclohexanols - pharmacology; Dose-Response Relationship, Drug; Drug Interactions - genetics; Drug Resistance, Multiple; Gene Expression - drug effects; Humans; indinavir; multi-drug resistance gene; Multidrug Resistance-Associated Proteins - genetics; P-glycoprotein; Polymerase Chain Reaction; rifampin; Rifampin - pharmacology; venlafaxine; Venlafaxine Hydrochloride
• ISSN: 0885-6222; 1099-1077
• DOI: 10.1002/hup.820

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. Copyright © 2007 John Wiley & Sons, Ltd.