Duchin K L, McKinstry D N, Cohen A I, Migdalof B H
Department of Human Pharmacology, E.R. Squibb & Sons, Inc., Princeton.
Clin Pharmacokinet. 1988 Apr;14(4):241-59. doi: 10.2165/00003088-198814040-00002.
Captopril, the first orally active inhibitor of angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. The pharmacokinetics of this agent have been studied extensively in healthy subjects and in patients with hypertension, congestive heart failure, and chronic renal failure. Captopril contains a sulphydryl group and binds readily to albumin and other plasma proteins. The drug also forms mixed disulphides with endogenous thiol-containing compounds (cysteine, glutathione), as well as the disulphide dimer of the parent compound. These components in blood and urine are measured collectively as total captopril. Because of the reversibility of the formation of these inactive disulphides, total captopril may serve as a reservoir of the pharmacologically active moiety, and thus contribute to a duration of action longer than that predicted by blood concentrations of unchanged captopril. To measure free or unchanged captopril concentrations, a chemical stabiliser must be added to the biological samples to prevent the formation of captopril disulphides ex vivo. In healthy subjects given captopril intravenously, the body clearance of captopril and steady-state volume of distribution were about 0.7 L/h/kg and 0.8 L/kg, respectively. The elimination half-life of unchanged captopril was approximately 2 hours. The primary route of elimination of captopril is the kidney. The renal clearance of unchanged captopril exceeds the glomerular filtration rate, due to active tubular secretion of the drug. In healthy subjects, about 70 to 75% of an oral dose is absorbed and the bioavailability of captopril is approximately 65%. Peak blood concentrations are reached about 45 to 60 minutes after oral administration. The bioavailability of captopril is not altered by age or concomitant medications including diuretics, procainamide, allopurinol, cimetidine or digoxin. However, the co-administration of food or antacids, or probenecid with captopril has been shown to diminish the bioavailability of the latter and decrease its clearance, respectively. The decreased bioavailability of captopril when taken with meals does not significantly alter clinical responses to the drug. Over a wide range of oral (10 to 150 mg) and intravenous doses (2.5 to 10 mg) captopril had linear kinetics in healthy volunteers. In healthy subjects with normal renal function and patients with congestive heart failure given captopril 3 times daily, blood concentrations of total captopril accumulated, whereas those of unchanged captopril did not. Severe renal insufficiency was associated with an accumulation of both unchanged and total captopril.(ABSTRACT TRUNCATED AT 400 WORDS)
卡托普利是首个口服有效的血管紧张素转换酶抑制剂，广泛用于治疗高血压和充血性心力衰竭。该药物的药代动力学已在健康受试者以及高血压、充血性心力衰竭和慢性肾衰竭患者中进行了广泛研究。卡托普利含有一个巯基，能迅速与白蛋白和其他血浆蛋白结合。该药还会与内源性含硫醇化合物（半胱氨酸、谷胱甘肽）以及母体化合物的二硫化物二聚体形成混合二硫化物。血液和尿液中的这些成分统称为总卡托普利。由于这些无活性二硫化物形成的可逆性，总卡托普利可作为药理活性部分的储存库，从而使作用持续时间长于由未改变的卡托普利血药浓度所预测的时间。为了测量游离或未改变的卡托普利浓度，必须向生物样品中添加化学稳定剂，以防止离体时卡托普利二硫化物的形成。在静脉注射卡托普利的健康受试者中，卡托普利的机体清除率和稳态分布容积分别约为0.7 L/h/kg和0.8 L/kg。未改变的卡托普利的消除半衰期约为2小时。卡托普利的主要消除途径是肾脏。由于药物的肾小管主动分泌，未改变的卡托普利的肾清除率超过肾小球滤过率。在健康受试者中，口服剂量的约70%至75%被吸收，卡托普利的生物利用度约为65%。口服给药后约45至60分钟达到血药浓度峰值。卡托普利的生物利用度不受年龄或包括利尿剂、普鲁卡因胺、别嘌醇、西咪替丁或地高辛在内伴随用药的影响。然而，已证明食物或抗酸剂或丙磺舒与卡托普利合用时，会分别降低后者的生物利用度并减少其清除率。进餐时服用卡托普利生物利用度降低，并不会显著改变药物的临床反应。在健康志愿者中，卡托普利在广泛的口服剂量（10至150 mg）和静脉剂量（2.5至10 mg）范围内呈线性动力学。在肾功能正常的健康受试者和每日服用3次卡托普利的充血性心力衰竭患者中，总卡托普利的血药浓度会累积，而未改变的卡托普利则不会。严重肾功能不全与未改变的卡托普利和总卡托普利的蓄积均有关。（摘要截选至400字）
