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 micromol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K(m) 72 micromol/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(tau) and C(max,ss) of digoxin, atorvastatin, o-hydroxy-atorvastatin, and rho-hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC(tau) 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.
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http://dx.doi.org/10.1177/0091270008323258 | DOI Listing |
Endocr Connect
January 2025
P Kamenický, Centre de Référence des Maladies Rares de l'Hypophyse, Le Kremlin-Bicêtre, 94275, France.
Background: Arterial hypertension and left ventricular hypertrophy and remodeling are independent cardiovascular risk factors in patients with Cushing's syndrome. Changes in the renin-angiotensin system and in the mineralocorticoid axis activity could be involved as potential mechanisms in their pathogenesis, in addition to cortisol excess.
Methods: In this ancillary study of our previous study prospectively investigating patients with ACTH-dependent Cushing's syndrome by cardiac magnetic resonance imaging (NCT02202902), 11 patients without any interfering medication were cross-sectionally compared to 20 control subjects matched for age, sex and body mass index.
Int J Mol Sci
December 2024
Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary.
The octapeptide angiotensin II (Ang II) is a circulating hormone as well as a locally formed agonist synthesized by the angiotensin-converting enzyme (ACE) of endothelial cells. It forms a powerful mechanism to control the amount and pressure of body fluids. All main effects are directed to save body salt and water and ensure blood pressure under basic conditions and in emergencies.
View Article and Find Full Text PDFEur J Heart Fail
January 2025
Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Aims: Guidelines recommend immediate initiation of all four class I guideline-directed medical therapies, renin-angiotensin system inhibitors (RASI) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) following the diagnosis of heart failure (HF) with reduced ejection fraction (HFrEF). The extent to which this occurs in new-onset HFrEF is unclear. We assessed guideline-recommended therapies during the first year following a HFrEF diagnosis.
View Article and Find Full Text PDFFront Nephrol
December 2024
Renal Pathophysiology Laboratory, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil.
In glomerulopathies, endothelial dysfunction and the presence of histological vascular lesions such as thrombotic microangiopathy, arteriolar hyalinosis, and arteriosclerosis are related to a severe clinical course and worse renal prognosis. The endothelial cell, which naturally has anti-inflammatory and anti-thrombotic regulatory mechanisms, is particularly susceptible to damage caused by various etiologies and can become dysfunctional due to direct/indirect injury or a deficiency of protective factors. In addition, endothelial regulation and protection involve participation of the complement system, factors related to angiogenesis, the renin-angiotensin system (RAS), endothelin, the glycocalyx, the coagulation cascade, interaction between these pathways, interactions between glomerular structures (the endothelium, mesangium, podocyte, and basement membrane) and interstitial structures (tubules, arterioles and small vessels).
View Article and Find Full Text PDFHeart Fail Rev
January 2025
Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland.
Heart failure (HF) represents a significant global health challenge, characterized by high morbidity and mortality rates, decreased quality of life and a significant financial and economic burden. The prevalence of HF continues to rise, driven by an ageing population and an increasing burden of comorbidities such as hypertension, diabetes and obesity. Understanding the complex pathophysiology and developing effective treatments are critical for improving patient outcomes, yet the range of effective, life-prolonging medication classes has remained mostly constant in the last few decades.
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