In marmosets lacking in sodium, oral aliskiren (< 10 mg/kg, daily) lowers blood pressure and inhibits plasma renin activity [2]. In BALB/c mice expressing C26 mouse colon cancer cells, aliskiren (10 mg/kg, once by gavage) can dramatically reduce a number of cachexia-related symptoms, such as weight loss, tumor burden, muscle atrophy, and muscle dysfunction. and decreased longevity [3].

Absorption, Distribution and Excretion
Aliskiren is absorbed in the gastrointestinal tract and is poorly absorbed with a bioavailability between 2.0 and 2.5%. Peak plasma concentrations of aliskiren are achieved between 1 to 3 hours after administration. Steady-state concentrations of aliskiren are achieved within 7-8 days of regular administration.
Aliskiren is mainly excreted via the hepatobiliary route and by oxidative metabolism by hepatic cytochrome enzymes. Approximately one-quarter of the absorbed dose appears in the urine as unchanged parent drug. One pharmacokinetic study of radiolabeled aliskiren detected 0.6% radioactivity in the urine and more than 80% in the feces, suggesting that aliskiren is mainly eliminated by the fecal route.
Unchanged aliskiren accounts for about 80% of the drug found in the plasma.
Aliskiren is partially cleared in the kidneys, and safety data have not been established for patients with a creatinine clearance of less than 30 mL/min. One pharmacokinetic study revealed an average renal clearance of 1280 +/- 500 mL/hour in healthy volunteers.
Poorly absorbed; oral bioavailability is about 2.5%.
Steady state blood levels are reached in about 7-8 days.
Peak plasma concentrations usually attained within 1-3 hours following oral administration. Substantial proportion (85-90%) of antihypertensive effect attained within 2 weeks of initiation of therapy.
High-fat meal decreases mean AUC and peak plasma concentration by 71 and 85%, respectively; however, in clinical studies drug was administered without requiring a fixed relation of administration to meals.
For more Absorption, Distribution and Excretion (Complete) data for Aliskiren (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
About 80% of the drug in plasma following oral administration is unchanged. Two major metabolites account for about 1-3% of aliskiren in the plasma. One metabolite is an O-demethylated alcohol derivative and the other is a carboxylic acid derivative. Minor oxidized and hydrolyzed metabolites may also be found in the plasma.
Amount of absorbed dose that undergoes metabolism not established; however, drug appears to undergo minimal hepatic metabolism. CYP isoenzyme 3A4 appears to be main enzyme responsible for metabolism of drug based on in vitro studies. Also, a substrate for p-glycoprotein.
The major metabolic pathways for aliskiren were O-demethylation at the phenyl-propoxy side chain or 3-methoxy-propoxy group, with further oxidation to the carboxylic acid derivative.
... The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. ...

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Biological Half-Life
Plasma half-life for aliskiren can range from 30 to 40 hours with an accumulation half-life of about 24 hours.
Accumulation half-life is approximately 24 hours.
... Terminal half-lives for radioactivity and aliskiren in plasma were 49 hr and 44 hr, respectively. ...
Terminal half-life is approximately 24-40 hours; wide interpatient variability observed.

Hepatotoxicity
Serum aminotransferase elevations during aliskiren therapy are uncommon and rates of such elevations have not been reported in the large clinical trials that demonstrated its efficacy in hypertension. An instance of serum aminotransferase elevation with jaundice was reported in the registration trials of aliskiren and several instances of marked serum enzyme elevations during therapy with few symptoms and without jaundice have been reported. In most instances, the pattern of enzyme elevation was distinctly hepatocellular and recovery was prompt once aliskiren was stopped. There have also been reports to the sponsor of severe hepatic reactions including hepatic failure and more recently a published case report of acute liver injury attributed to this agent. The latency to onset has ranged from 1 to 6 months and the pattern of injuryis typically cholestatic or mixed. Most cases have been mild to moderate in severity and marked by rapid recovery once aliskiren is stopped.
Likelihood score: C (probable cause of clinically apparent liver injury).

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Protein Binding
The plasma protein binding of aliskiren ranges from 47-51%.

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Interactions
Furosemide: When aliskiren was coadministered with furosemide, the AUC and Cmax of furosemide were reduced by about 30% and 50%, respectively. Patients receiving furosemide could find its effect diminished after starting aliskiren.
Verapamil: Coadministration of 240 mg of verapamil with 300 mg aliskiren resulted in an approximately 2-fold increase in Cmax and AUC of aliskiren. However, no dosage adjustment is necessary.
Cyclosporine: Coadministration of 200 mg and 600 mg cyclosporine with 75 mg aliskiren resulted in an approximately 2.5-fold increase in Cmax and 5-fold increase in AUC of aliskiren. Concomitant use of aliskiren with cyclosporine is not recommended.
Ketoconazole: Coadministration of 200 mg twice-daily ketoconazole with aliskiren resulted in an approximate 80% increase in plasma levels of aliskiren. A 400-mg once-daily dose was not studied but would be expected to increase aliskiren blood levels further.
For more Interactions (Complete) data for Aliskiren (11 total), please visit the HSDB record page.

[1]. Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor. ACS Med. Chem. Lett., 2012, 3 (9), pp 754–758.

[2]. Structure-based design of aliskiren, a novel orally effective renin inhibitor.Biochem Biophys Res Commun, 2003, 308(4), 698-705.

[3]. Aliskiren targets multiple systems to alleviate cancer cachexia. Oncol Rep. 2016 Nov;36(5):3014-3022.

[4]. Interplay between brain stem angiotensins and monocyte chemoattractant protein-1 as a novel mechanism for pressor response after ischemic stroke. Neurobiol Dis. 2014 Nov;71:292-304.

[5]. Pharmacokinetics and pharmacodynamics of aliskiren, an oral direct renin inhibitor. Pharmacol Rep. 2008 Sep-Oct;60(5):623-31.

[6]. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation, 2005, 111(8), 1012-1018.

Therapeutic Uses
Antihypertensive Agent; Renin/antagonists and inhibitors
Tekturna is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. Use with maximal doses of ACE inhibitors has not been adequately studied. /Included in US product label/

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Drug Warnings
/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Tekturna as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Possible fetal and neonatal morbidity and mortality when used during pregnancy. Such potential risks occur throughout pregnancy, especially during the second and third trimesters.
Retrospective data indicate that angiotensin-converting enzyme (ACE) inhibitors, a class of drugs acting on the renin-angiotensin-aldosterone (RAA) system, have been associated with an increased risk of major congenital malformations when administered during the first trimester of pregnancy.
Excessive hypotension reported rarely in patients with uncomplicated hypertension receiving the drug alone and infrequently during combination therapy with other antihypertensive agents.
For more Drug Warnings (Complete) data for Aliskiren (21 total), please visit the HSDB record page.

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Pharmacodynamics
Aliskiren reduces blood pressure by inhibiting renin. This leads to a cascade of events that decreases blood pressure, lowering the risk of fatal and nonfatal cardiovascular events including stroke and myocardial infarction.

C₃₀H₅₃N₃O₆

551.76

551.393

173334-57-1

Aliskiren hemifumarate;173334-58-2;Aliskiren hydrochloride;173399-03-6;Aliskiren-d6 hydrochloride;1246815-96-2;Aliskiren fumarate;1196835-68-3;Aliskiren-d6 hemifumarate

5493444

White to light yellow solid powder

1.1±0.1 g/cm3

748.4±60.0 °C at 760 mmHg

>95

406.4±32.9 °C

0.0±2.6 mmHg at 25°C

1.514

2.74

4

7

19

39

717

4

CC(C)[C@@H](CC1=CC(=C(C=C1)OC)OCCCOC)C[C@@H]([C@H](C[C@@H](C(C)C)C(=O)NCC(C)(C)C(=O)N)O)N

UXOWGYHJODZGMF-QORCZRPOSA-N

InChI=1S/C30H53N3O6/c1-19(2)22(14-21-10-11-26(38-8)27(15-21)39-13-9-12-37-7)16-24(31)25(34)17-23(20(3)4)28(35)33-18-30(5,6)29(32)36/h10-11,15,19-20,22-25,34H,9,12-14,16-18,31H2,1-8H3,(H2,32,36)(H,33,35)/t22-,23-,24-,25-/m0/s1

(2S,4S,5S,7S)-5-amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-7-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-8-methyl-2-propan-2-ylnonanamide

CGP-60536B SPP100 CGP 60536 SPP-100CGP60536B SPP 100

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Ethanol : ~100 mg/mL (~181.24 mM)
DMSO : ~100 mg/mL (~181.24 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)