Rosenkranz B, Winkelmann B R, Parnham M J
Hoechst AG, Frankfurt am Main, Germany.
Clin Pharmacokinet. 1996 May;30(5):372-84. doi: 10.2165/00003088-199630050-00004.
Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with counterclockwise hysteresis, i.e. a greater effect associated with the decrease of plasma concentrations than during their increase, which may be at least partly due to the metabolic delay in the formation of NO from SIN-1. Accordingly, the duration of action of molsidomine is longer than would be expected on the basis of the elimination half-life. The pharmacokinetics of molsidomine support the recommended dosages for use in angina pectoris.
莫西多明是一种用于生成一氧化氮（NO）的前体药物。其药代动力学特点是吸收和水解迅速，母体化合物及其活性代谢产物SIN-1在短时间内即可达到最大全身浓度。血浆药物浓度达峰时间（tmax）为1至2小时。以片剂形式口服给药后，母体化合物的生物利用度为44%至59%，但进一步代谢以释放NO并形成极性代谢产物的过程很快；SIN-1的半衰期（t-1/2）为1至2小时。尿排泄占所给药量中未原样排泄部分的90%以上。母体化合物的蛋白结合率很低（3%至11%），其分布容积（Vd）与体重范围相对应。单剂量研究（1、2和4毫克）显示药代动力学呈线性，健康个体（每日3次，每次2毫克，共7天）和冠状动脉疾病（CAD）患者（每日4次，每次4毫克，共4周）的多剂量研究未显示该药物有任何蓄积。一项针对年轻人和老年人的研究表明，首过效应随年龄增长而降低，t-1/2延长，导致莫西多明和SIN-1的浓度-时间曲线下面积（AUC）增加。在肝病和充血性心力衰竭患者中观察到类似变化，但在CAD患者中变化较小。肝病患者的清除率也受损，但肾功能受损并未显著改变莫西多明的药代动力学。一般来说，由于治疗剂量范围较大，根据临床经验无需调整剂量。在某些患者中，可能建议采用较低的起始剂量，如肝功能或肾功能受损、充血性心力衰竭患者或同时使用其他血管活性化合物治疗的患者。观察到线性剂量-效应关系并伴有逆时针滞后现象，即与血浆浓度降低相关的效应大于浓度升高时的效应，这可能至少部分归因于SIN-1生成NO过程中的代谢延迟。因此，莫西多明的作用持续时间比根据消除半衰期预期的要长。莫西多明的药代动力学支持其用于心绞痛的推荐剂量。
