Objective: In animals, the direct renin inhibitor aliskiren showed extensive tissue binding in the kidney and long-lasting renal effects. Aliskiren provides prolonged blood pressure-lowering effects following treatment discontinuation in patients. Therefore, we investigated whether aliskiren attains tissue concentrations sufficient to inhibit local renin–angiotensin system (RAS) activity in patients.
Methods: We included 10 hypertensive patients with abdominal adiposity in an open-label study. Following 1–2 weeks washout, patients received 2 weeks placebo, then 4 weeks aliskiren 300 mg once daily, followed by 4 weeks washout, and then 4 weeks amlodipine 5 mg once daily. Drug concentrations and RAS biomarkers were measured in interstitial fluid using microdialysis and in biopsies from abdominal subcutaneous adipose and skeletal muscle.
Results: We detected aliskiren in all compartments. After 4 weeks of treatment, microdialysate aliskiren concentrations (ng/ml) were 2.4 ± 2.1 (adipose) and 7.1 ± 4.2 (skeletal muscle), similar to plasma concentrations (8.4 ± 4.4); tissue concentrations (ng/g) were 29.0 ± 16.7 (adipose) and 107.3 ± 68.6 (skeletal muscle). Eight weeks after discontinuation, aliskiren was measurable in tissue biopsies but not in plasma or in interstitial fluid. Pooled microdialysate samples from two sets of four patients suggested reduction in tissue angiotensin II with aliskiren but not with amlodipine.
Conclusion: In obese hypertensive patients, aliskiren penetrates adipose and skeletal muscle tissue at levels that are apparently sufficient to reduce tissue RAS activity. Furthermore, tissue binding may contribute to aliskiren's prolonged blood pressure-lowering effect following discontinuation.
aFranz Volhard Clinical Research Center, Charité, Berlin, Germany
bCentre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
cInstitute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
dErasmus MC, Rotterdam, The Netherlands
eNovartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
fNovartis Institutes for BioMedical Research, Basel, Switzerland
Correspondence to Jens Jordan, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. Tel: +49 511 532 2820; fax: +49 511 532 2750; e-mail: firstname.lastname@example.org
Abbreviation: RAS, renin–angiotensin system
This work has been presented partly at American Diabetes Association 2010 and European Society of Hypertension 2011 meetings.
Received 28 October, 2011
Accepted 18 November, 2011