Cirillo Iolanda, Martin Nancy E, Brennan Barbara, Barrett Jeffrey S
Drug Metabolism and Pharmacokinetics, Aventis Pharmaceuticals, Inc, 1041 Route 202-206, PO Box 6800, Mail stop M303B, Bridgewater, NJ 08807-0800, USA.
J Clin Pharmacol. 2004 Dec;44(12):1379-84. doi: 10.1177/0091270004269557.
M100240 is a thioester of MDL 100,173, a dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor. Clinical studies have shown that M100240 is capable of decreasing ACE activity and angiotensin II concentrations while increasing plasma renin activity and potentiating the effects of atrial natriuretic peptide. This may result in a unique treatment benefit in disease states characterized by intravascular volume or sodium overload or increased venous pressure. The pharmacokinetics of MDL 100,173 were evaluated in 30 healthy subjects in an open-label, randomized, 2-period crossover design. Subjects received a single oral dose of 50 mg of M100240 administered with a high-fat meal and separately under fasted conditions. Serial plasma concentrations of M100240 and MDL 100,173 were analyzed, and pharmacokinetic parameters were calculated with noncompartmental methods. The intrasubject percent coefficient of variation for MDL 100,173 C(max) and AUC(0-24h) were less than 20%, indicating that this agent is a moderately variable drug. Although AUC(0-24h) was within the protocol-defined range of 80% to 125%, the lower limit of the 90% confidence interval for C(max) fell outside of the 70% to 143% range. Absence of a food effect on the pharmacokinetic profile of 50 mg of M100240 could therefore not be demonstrated. This finding is not surprising based on the documented food effect with the sulfhydryl-containing ACE inhibitor, captopril. Clinical significance of this pharmacokinetic food effect is unlikely, as the magnitude of pharmacodynamic response is probably better correlated with AUC than a single-point determination of C(max). Single oral doses of 50 mg of M100240 were safe and well tolerated under fed and fasted conditions.
M100240是MDL 100,173的硫酯，MDL 100,173是一种双功能血管紧张素转换酶（ACE）/中性内肽酶（NEP）抑制剂。临床研究表明，M100240能够降低ACE活性和血管紧张素II浓度，同时增加血浆肾素活性并增强心房利钠肽的作用。这可能在以血管内容量或钠超负荷或静脉压升高为特征的疾病状态中带来独特的治疗益处。在一项开放标签、随机、两期交叉设计中，对30名健康受试者评估了MDL 100,173的药代动力学。受试者分别在高脂餐和空腹条件下接受单次口服50 mg M100240。分析了M100240和MDL 100,173的系列血浆浓度，并用非房室方法计算药代动力学参数。MDL 100,173的C(max)和AUC(0 - 24h)的受试者内变异系数百分比小于20%，表明该药物是一种中等变异药物。尽管AUC(0 - 24h)在方案定义的80%至125%范围内，但C(max)的90%置信区间下限落在70%至143%范围之外。因此，无法证明50 mg M100240的药代动力学特征不受食物影响。基于含巯基的ACE抑制剂卡托普利已记录的食物影响，这一发现并不令人惊讶。这种药代动力学食物影响的临床意义不大，因为药效学反应的程度可能与AUC的相关性比C(max)的单点测定更好。在进食和空腹条件下，单次口服50 mg M100240是安全且耐受性良好的。
