Waldmeier Felix, Glaenzel Ulrike, Wirz Bernard, Oberer Lukas, Schmid Dietmar, Seiberling Michael, Valencia Jessica, Riviere Gilles-Jacques, End Peter, Vaidyanathan Sujata
Novartis Pharma AG, Basel, Switzerland.
Drug Metab Dispos. 2007 Aug;35(8):1418-28. doi: 10.1124/dmd.106.013797. Epub 2007 May 17.
Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) is the first in a new class of orally active, nonpeptide direct renin inhibitors developed for the treatment of hypertension. The absorption, distribution, metabolism, and excretion of [(14)C]aliskiren were investigated in four healthy male subjects after administration of a single 300-mg oral dose in an aqueous solution. Plasma radioactivity and aliskiren concentration measurements and complete urine and feces collections were made for 168 h postdose. Peak plasma levels of aliskiren (C(max)) were achieved between 2 and 5 h postdose. Unchanged aliskiren represented the principal circulating species in plasma, accounting for 81% of total plasma radioactivity (AUC(0-infinity)), and indicating very low exposure to metabolites. Terminal half-lives for radioactivity and aliskiren in plasma were 49 h and 44 h, respectively. Dose recovery over 168 h was nearly complete (91.5% of dose); excretion occurred almost completely via the fecal route (90.9%), with only 0.6% recovered in the urine. Unabsorbed drug accounted for a large dose proportion recovered in feces in unchanged form. Based on results from this and from previous studies, the absorbed fraction of aliskiren can be estimated to approximately 5% of dose. The absorbed dose was partly eliminated unchanged via the hepatobiliary route. Oxidized metabolites in excreta accounted for at least 1.3% of the radioactive dose. 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.
阿利吉仑（2(S),4(S),5(S),7(S)-N-(2-氨基甲酰基-2-甲基丙基)-5-氨基-4-羟基-2,7-二异丙基-8-[4-甲氧基-3-(3-甲氧基丙氧基)苯基]-辛酰胺半富马酸盐）是为治疗高血压而研发的新型口服活性非肽类直接肾素抑制剂中的首个药物。在4名健康男性受试者中，以水溶液形式单次口服300毫克剂量后，研究了[(14)C]阿利吉仑的吸收、分布、代谢和排泄情况。给药后168小时进行血浆放射性和阿利吉仑浓度测量，并收集完整的尿液和粪便。给药后2至5小时达到阿利吉仑的血浆峰值水平（C(max)）。未变化的阿利吉仑是血浆中的主要循环成分，占血浆总放射性（AUC(0-无穷大)）的81%，表明对代谢物的暴露极低。血浆中放射性和阿利吉仑的终末半衰期分别为49小时和44小时。168小时内的剂量回收率几乎达到100%（剂量的91.5%）；排泄几乎完全通过粪便途径（90.9%），仅0.6%在尿液中回收。未吸收的药物以未变化的形式在粪便中占回收剂量的很大比例。根据本研究及先前研究的结果，阿利吉仑的吸收分数估计约为剂量的5%。吸收的剂量部分通过肝胆途径以未变化的形式消除。排泄物中的氧化代谢物至少占放射性剂量的1.3%。阿利吉仑的主要代谢途径是苯丙氧基侧链或3-甲氧基丙氧基的O-去甲基化，并进一步氧化为羧酸衍生物。
