Allikmets leaving the other types of AT receptors (eg, AT2R and AT4R) that might be involved in some important regulatory func- tions of the endothelium, unopposed to potential stimulation by Ang II (Watanabe et al 2005). Importantly, along with the incomplete blockade of RAAS, both ACE inhibitors and ARBs lead to a substantial compensatory raise in the circulat- ing active renin and angiotensin peptides that may eventually limit their therapeutic potential (Stanton 2003). Renin is the rate-limiting step of the RAAS and has unique speciﬁcity for its substrate, angiotensinogen. Inhibi- tion of renin has long ago been recognised as an attractive option that would block the RAAS at the highest level, at its origin. Thus, the formation of both Ang I and Ang II is blocked, there is no activation of the AT receptors and no interference with bradykinin metabolism. It has been shown that a rise in circulating renin occurs, but the activity of the released enzyme is blocked in the presence of renin inhibitors (Nussberger et al 2002; Azizi et al 2004). The ﬁrst renin inhibitors were synthesized already more than 30-years ago (Gross et al 1971). First orally active compounds were developed in the 1980s, including enalkiren (A 64662; Abbott, Abbott Park, IL, USA), CGP38560A (Ciba-Geigy, Basel, Switzerland), remikiren (Ro 425892; Hoffmann-La Roche, Basel, Switzerland), and zankiren (A 72517; Abbott). However, poor absorption from the gas- trointestinal tract (with bioavailability of less than 2%), short half-life and low potency prevented further development of these compounds (Staessen et al 2006). Aliskiren is the ﬁrst in a new class of orally active, non- peptide, low molecular weight renin inhibitors, and so far the only renin inhibitor that has progressed to phase III clinical trials. Aliskiren (formerly CGP 60536) was discovered in Ciba-Geigy (now Novartis, Basel, Switzerland) through a combination of molecular modeling and crystallographic structure analysis (Wood et al 2003). The synthetic pathway at that time was not suitable for large-scale manufacturing and the compound was out-licenced to Speedel AG (Basel, Switzerland) where a new cost-effective manufacturing method for aliskiren (SPP 100) was developed and preclinical and early clinical testing successfully performed. Novartis exercised its call-back option for further development of aliskiren in phase III trials (Wood et al 2003). Aliskiren was approved in 2007 by regulatary bodies both in Europe and in the US, for use alone as with others agents in the treatment of arterial hypertension. This review summarizes the available data on the pharma- cokinetic and pharmacodynamic properties of aliskiren and its clinical development for treatment of arterial hypertension. 810 Pharmacokinetic properties Aliskiren is a transition-state mimetic, with favourable physico-chemical properties including high aqueous solubility ( 350 mg/ml at pH 7.4) and high hydrophilicity (log Poct/ water = 2.45 at pH 7.4). These properties are important prereq- uisites for improved oral bioavailability (Wood et al 2003). Aliskiren pharmacokinetics has been studied in marmosets. After a single oral dose of 10 mg/kg, peak plasma concentra- tions were reached in 1–2 hours. The calculated bioavailability was 16.3% and mean half-life 2.3 h (Wood et al 2005). The single and multiple-dose oral pharmacokinetics of aliskiren have been investigated over the dose range 40–1800 mg in healthy male subjects (Azizi et al 2006). Study in healthy volunteers (n = 18) showed that the plasma concentration increased dose-dependently after oral aliskiren in doses of 40–640 mg/day, with peak concentrations reached in 3–6 h. The mean plasma half-life was 23.7 h (with SD of 7.6h and range 20–45 h). The oral bioavailability of the hard gelatine 75 mg capsule was 2.6%. Plasma steady-state concentrations were reached after 5–8 days of treatment (Nussberger et al 2002). Aliskiren accumulates following multiple once-daily administration as indicated by the accumulation ratios of between 1.4 and 3.9, with the accumulation being more pronounced at higher doses (Azizi et al 2006). Aliskiren pharmacokinetics is dependent on food intake. Thus, aliskiren 150 mg orally with food results in mean Cmax and AUC0–∞ values by 81 and 62% lower, respectively, when compared to the fasting state (Azizi et al 2006). Aliskiren pharmacokinetics after a single dose of 300 mg has been examined in type-2 diabetic patients (n = 30) versus healthy volunteers (n = 30) and no signiﬁcant differences were observed. Also, no signiﬁcant correlation between glycaemic control (% glycosylated haemoglobin) and any of the measured pharmacokinetic parameters were detected (Zhao et al 2006). Aliskiren demonstrated similar pharmacokinetic and pharmacodynamic properties in Japanese and Caucasian subjects (Vaidyanathan, Jermany et al 2007). At steady state, peak PRC level and AUC for the concentration-time plot were not signiﬁcantly different (p = 0.64 and p = 0.80, respec- tively) and PRA was reduced to a similar extent (by 87.5% and 85.7%, respectively, compared with baseline; p 0.01). Aliskiren was well tolerated by both ethnic groups. Aliskiren is mainly eliminated unmetabolized via biliary excretion, with less than 1% excreted in the urine (de Gasparo et al 1989). Aliskiren binds only moderately to plasma proteins (mean protein-bounding level of 49.5%), with the Vascular Health and Risk Management 2007:3(6)