Shah Bharti, Emmons Gary, Rohatagi Shashank, Martin Nancy E, Jensen Bradford K
Drug Metabolism & Pharmacokinetics, Aventis Pharmaceuticals Inc., Bridgewater, New Jersey 08807, USA.
Am J Ther. 2003 Sep-Oct;10(5):356-62. doi: 10.1097/00045391-200309000-00008.
[4S-[4alpha,7alpha(R*),12bbeta]]-7[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylic acid (M100240) is an acetate thioester of MDL 100,173-a dual angiotensin-converting enzyme/neutral endopeptidase inhibitor currently in phase II development. The mass balance of [(14)C]M100240 was assessed following oral administration of [(14)C]M100240. Healthy male subjects were given a single 25-mg dose of [(14)C]M100240 (50 microCi) as an oral solution under fasting conditions. Blood samples and excreta were collected postdose. (14)C-radioactivity was measured by liquid scintillation counting. Plasma concentrations of M100240 and MDL 100,173 were determined by LC/MS/MS methods. Pharmacokinetic parameters were calculated. About 98% of the total radioactive dose was recovered within 7 days of oral administration, with most of the radioactivity recovered within 72 hours. Of the recovered radioactive dose, 49.4% and 48.5% were recovered in the urine and feces, respectively. Unchanged M100240 and MDL 100,173 were not detected in the excreta. On average, 76% of the total radioactivity in the blood was associated with the plasma fraction. M100240 accounted for less than 0.06% of the (14)C-radioactivity in plasma and MDL 100,173 accounted for 15.8% (AUC( infinity )) of (14)C-radioactivity in plasma after oral dosing. These data suggest that the drug was absorbed but rapidly converted to its metabolites either presystemically or postsystemically. Up to 78% of the total radioactivity was identified as MDL 100,173. The apparent terminal elimination half-life of MDL 100,173 was longer than that of (14)C-radioactivity, attributable to assay sensitivity and the saturable binding phenomenon commonly associated with angiotensin-converting enzyme inhibitors. M100240 undergoes extensive metabolism in humans, and its metabolites are excreted relatively equally in feces and urine.
[4S-[4α,7α(R*),12ββ]]-7[[2-(乙酰硫基)-1-氧代-3-苯基丙基]氨基]-1,2,3,4,6,7,8,12b-八氢-6-氧代-吡啶并[2,1-a][2]苯并氮杂卓-4-羧酸（M100240）是MDL 100,173的乙酸硫酯，MDL 100,173是一种双重血管紧张素转换酶/中性内肽酶抑制剂，目前正处于II期开发阶段。在口服给予[(14)C]M100240后评估[(14)C]M100240的质量平衡。在禁食条件下，健康男性受试者口服单剂量25mg的[(14)C]M100240（50微居里）溶液。给药后收集血样和排泄物。通过液体闪烁计数法测量(14)C放射性。采用LC/MS/MS方法测定M100240和MDL 100,173的血浆浓度。计算药代动力学参数。口服给药后7天内回收了约98%的总放射性剂量，大部分放射性在72小时内回收。在回收的放射性剂量中，分别有49.4%和48.5%在尿液和粪便中回收。排泄物中未检测到未变化的M100240和MDL 100,173。平均而言，血液中76%的总放射性与血浆部分相关。口服给药后，M100240占血浆中(14)C放射性的比例不到0.06%，MDL 100,173占血浆中(14)C放射性的15.8%（AUC(无穷大)）。这些数据表明该药物被吸收，但在体循环前或体循环后迅速转化为其代谢产物。高达78%的总放射性被鉴定为MDL 100,173。MDL 100,173的表观终末消除半衰期比(14)C放射性的长，这归因于检测灵敏度以及血管紧张素转换酶抑制剂常见的饱和结合现象。M100240在人体内经历广泛代谢，其代谢产物在粪便和尿液中的排泄相对均匀。
