Singhvi S M, Foley J E, Willard D A, Morrison R A
Department of Drug Metabolism, Squibb Institute for Medical Research, Princeton, NJ.
J Pharm Sci. 1990 Nov;79(11):970-3. doi: 10.1002/jps.2600791105.
Zofenopril calcium (1) is a prodrug that is hydrolyzed in vivo to the active angiotensin-converting enzyme (ACE) inhibitor SQ 26,333 (2). In a two-way crossover study, six healthy male subjects (age range 25-36 years) each received an iv 11.2-mg dose of [14C]SQ 26,703 (14C-3; the L-arginine salt of 2) and an oral 10-mg (equimolar) dose of 14C-1. After the iv dose of 14C-3, the 0-96-h recovery of radioactivity averaged 76 and 16% of the dose in urine and feces, respectively, indicating substantial biliary secretion. After the oral dose of 14C-1, excretion of radioactivity averaged 70% (urine) and 26% (feces). Negligible amounts of 1 were present in urine, indicating complete hydrolysis of the orally administered prodrug. The oral absorption of 1 was almost complete and the oral bioavailability of 2 averaged approximately 70%. The terminal elimination half-life for 2 after the iv dose averaged 5.5 h. Whole body clearance, renal clearance, nonrenal clearance, and Vdss averaged 11.4, 3.1, and 8.3 mL/min/kg and 1.3 L/kg, respectively. These data indicated that 2 is eliminated by the kidney as well as the liver, is extensively metabolized, and is distributed extensively into extravascular sites.
佐芬普利钙（1）是一种前药，在体内水解为活性血管紧张素转换酶（ACE）抑制剂SQ 26,333（2）。在一项双向交叉研究中，六名健康男性受试者（年龄范围25 - 36岁）每人静脉注射11.2毫克剂量的[14C]SQ 26,703（14C - 3；2的L - 精氨酸盐）和口服10毫克（等摩尔）剂量的14C - 1。静脉注射14C - 3后，0 - 96小时放射性回收率在尿液和粪便中分别平均为剂量的76%和16%，表明有大量胆汁分泌。口服14C - 1后，放射性排泄平均为70%（尿液）和26%（粪便）。尿液中1的含量可忽略不计，表明口服前药已完全水解。1的口服吸收几乎完全，2的口服生物利用度平均约为70%。静脉注射后2的终末消除半衰期平均为5.5小时。全身清除率、肾清除率、非肾清除率和稳态分布容积分别平均为11.4、3.1和8.3毫升/分钟/千克以及1.3升/千克。这些数据表明2通过肾脏和肝脏消除，广泛代谢，并广泛分布到血管外部位。
