HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Sign In to gain access to subscriptions and/or personal tools.

This Article Full Text Full Text (PDF) All Versions of this Article: 0091270008323258v1 48/11/1323    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vaidyanathan, S. Articles by Dole, W. P. Search for Related Content PubMed PubMed Citation Articles by Vaidyanathan, S. Articles by Dole, W. P. Social Bookmarking                         What's this?

Pharmacokinetics of the Oral Direct Renin Inhibitor Aliskiren in Combination With Digoxin, Atorvastatin, and Ketoconazole in Healthy Subjects: The Role of P-Glycoprotein in the Disposition of Aliskiren

From Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (Dr Vaidyanathan, Ms Reynolds, Dr Yeh, Dr Howard); Novartis Pharma AG, Basel, Switzerland (Dr Camenisch, Dr Schuetz, Dr Dieterich); Novartis Pharma SAS, Rueil-Malmaison, France (Dr Bizot); and Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (Dr Dole).

This study investigated the potential pharmacokinetic interaction between the direct renin inhibitor aliskiren and modulators of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Aliskiren stimulated in vitro P-glycoprotein ATPase activity in recombinant baculovirus-infected Sf9 cells with high affinity (K_m 2.1 µmol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K_m 72 µmol/L). Three open-label, multiple-dose studies in healthy subjects investigated the pharmacokinetic interactions between aliskiren 300 mg and digoxin 0.25 mg (n = 22), atorvastatin 80 mg (n = 21), or ketoconazole 200 mg bid (n = 21). Coadministration with aliskiren resulted in changes of <30% in AUC and C_max,ss of digoxin, atorvastatin, o-hydroxy-atorvastatin, and -hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC was significantly increased by coadministration with atorvastatin (by 47%, P < .001) or ketoconazole (by 76%, P < .001) through mechanisms most likely involving transporters such as P-glycoprotein and organic anion-transporting peptide and possibly through metabolic pathways such as CYP3A4 in the gut wall. These results indicate that aliskiren is a substrate for but not an inhibitor of P-glycoprotein. On the basis of the small changes in exposure to digoxin and atorvastatin and the <2-fold increase in exposure to aliskiren during coadministration with atorvastatin and ketoconazole, the authors conclude that the potential for clinically relevant drug interactions between aliskiren and these substrates and/or inhibitors of P-glycoprotein/CPY3A4/OATP is low.

Key Words: Cytochrome P450 • direct renin inhibitor • drug interaction • P-glycoprotein

Address for reprints: William P. Dole, MD, Novartis Institutes for Biomedical Research, 400 Technology Square, Building 605-820, Cambridge, MA 02139; e-mail: bill.dole{at}novartis.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J. M. A. Delou, A. G. Lopes, and M. A.M. Capella Unveiling the Role of Multidrug Resistance Proteins in Hypertension Hypertension, August 1, 2009; 54(2): 210 - 216. [Full Text] [PDF]