Migdalof B H, Antonaccio M J, McKinstry D N, Singhvi S M, Lan S J, Egli P, Kripalani K J
Drug Metab Rev. 1984;15(4):841-69. doi: 10.3109/03602538409041080.
By inhibiting ACE, captopril blocks the conversion of AI or AII and augments the effects of bradykinin both in vitro and in vivo. In rats, dogs, and monkeys with 2-kidney renal hypertension, orally administered captopril rapidly and markedly reduces blood pressure; this antihypertensive effect apparently occurs via a renin-dependent mechanism; that is, the inhibition of ACE. In 1-kidney renal hypertension studies in rats and dogs, it was determined that oral doses of captopril markedly lowered blood pressure, but only after several days of dosing; the mechanism is thought to be non-renin dependent. In SHR, daily oral doses of captopril progressively lowered blood pressure; normal levels were attained by the sixth month. In all species studied, the reduction in blood pressure resulted from a reduction in total peripheral resistance; cardiac output remained unchanged or increased. In humans, captopril reduces blood pressure in patients with essential hypertension with low, normal, and high renin levels, and in patients with renovascular hypertension and hypertension associated with chronic renal failure. In hypertensive patients with high plasma renin activity, captopril apparently exerts most of its pharmacologic effects through inhibition of ACE. The means by which captopril reduces high blood pressure associated with low or normal PRA is not known, but it is clear that captopril does not act on an overactive plasma renin-angiotensin system in these cases. The antihypertensive effect of captopril is enhanced when it is given in combination with a diuretic or after salt depletion. Captopril was rapidly and well absorbed in all species tested, including man. Studies in rodents indicated that ingestion of food caused a reduction in the extent of absorption and bioavailability of captopril. Captopril and/or its metabolites were distributed extensively and rapidly throughout most tissues of normal rats; no radioactivity was detected in the brain. In vitro and in vivo, captopril formed disulfide bonds with albumin and other proteins. This binding was reversible in nature. In vitro studies in blood indicates that the disulfide dimer of captopril and mixed disulfides of captopril with L-cysteine and glutathione were formed. In intact blood cells, captopril remained in the reduced form (sulfhydryl), whereas in whole blood or plasma, captopril was converted to its disulfide dimer and other oxidative products. Biotransformation of captopril may involve both enzymatic and nonenzymatic processes.(ABSTRACT TRUNCATED AT 400 WORDS)
通过抑制血管紧张素转换酶（ACE），卡托普利可阻断血管紧张素I（AI）或血管紧张素II（AII）的转化，并在体内外增强缓激肽的作用。在患有两肾肾性高血压的大鼠、犬和猴中，口服卡托普利可迅速且显著降低血压；这种降压作用显然是通过肾素依赖性机制产生的，即抑制ACE。在大鼠和犬的单肾肾性高血压研究中，确定口服卡托普利能显著降低血压，但仅在给药数天后出现；其机制被认为是非肾素依赖性的。在自发性高血压大鼠（SHR）中，每日口服卡托普利可使血压逐渐降低；到第六个月时达到正常水平。在所有研究的物种中，血压降低是由于总外周阻力降低所致；心输出量保持不变或增加。在人类中，卡托普利可降低肾素水平低、正常和高的原发性高血压患者以及肾血管性高血压和与慢性肾衰竭相关的高血压患者的血压。在血浆肾素活性高的高血压患者中，卡托普利显然通过抑制ACE发挥其大部分药理作用。卡托普利降低与低或正常血浆肾素活性（PRA）相关的高血压的机制尚不清楚，但很明显，在这些情况下卡托普利并非作用于过度活跃的血浆肾素 - 血管紧张素系统。当卡托普利与利尿剂联合使用或在限盐后给药时，其降压作用增强。卡托普利在包括人类在内的所有受试物种中吸收迅速且良好。在啮齿动物中的研究表明，摄入食物会导致卡托普利的吸收程度和生物利用度降低。卡托普利及其代谢产物在正常大鼠的大多数组织中广泛且迅速分布；在脑中未检测到放射性。在体内外，卡托普利与白蛋白和其他蛋白质形成二硫键。这种结合本质上是可逆的。血液中的体外研究表明，形成了卡托普利的二硫二聚体以及卡托普利与L - 半胱氨酸和谷胱甘肽的混合二硫键。在完整血细胞中，卡托普利保持还原形式（巯基），而在全血或血浆中，卡托普利转化为其二硫二聚体和其他氧化产物。卡托普利的生物转化可能涉及酶促和非酶促过程。（摘要截短至400字）
