Details

Autor(en) / Beteiligte

• Ejsing, Thomas B.
• Pedersen, Anne D.
• Linnet, Kristian

Titel

P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-drug interaction experiments

Ist Teil von

• Human psychopharmacology, 2005-10, Vol.20 (7), p.493-500

Ort / Verlag

Chichester, UK: John Wiley & Sons, Ltd

Erscheinungsjahr

2005

Quelle

Access via Wiley Online Library

Beschreibungen/Notizen

• The drug transporter P‐glycoprotein (P‐gp) influences drug distribution across the blood‐brain barrier (BBB) by actively extruding drugs into the neural capillaries. Several psychotropic drugs, including nortriptyline (NT) and risperidone (Risp), are substrates of P‐gp. Here we compared the in vitro P‐gp interactions of Risp and its major metabolite, 9‐OH‐Risperidone (OH‐Risp), with their distribution over the BBB in P‐gp knock‐out mice and in rats where P‐gp was inhibited. Km and Vmax were determined by an in vitro ATPase assay, and Vmax/Km ratios of 2.7 and 0.5 were recorded for Risp and OH‐Risp, respectively, suggesting that Risp is a better substrate for P‐gp than OH‐Risp. In Mdr1a (−/−) knock‐out mice, the brain‐serum ratios of both Risp and OH‐Risp were more than ten times those of control mice (14 and 11, respectively). When P‐gp was inhibited with cyclosporine A (CsA) in Wistar rats, the effect was an order of magnitude less than that observed for the knock‐out mice experiments (1–1.5 times the controls), and co‐administration of NT had no effect. In conclusion, both Risp and OH‐Risp interact with P‐gp in vitro, and P‐gp has a profound effect on Risp and OH‐Risp distribution over the BBB, as is evident from the knock‐out mice experiments. Drug–drug interaction effects in relation to P‐gp, however, appear to be more limited. Copyright © 2005 John Wiley & Sons, Ltd.