Marzo Antonio, Zava Dario, Coa Katrin, Dal Bo Lorenzo, Ismaili Shefqet, Tavazzi Simona, Cantoni Vittorio
Clinical Pharmacology Unit, I.P.A.S. SA, Via Mastri 36, 6853 Ligornetto, Switzerland.
Arzneimittelforschung. 2009;59(9):455-60. doi: 10.1055/s-0031-1296425.
Isoxsuprine (1-(4-hydroxyphenyl)-2-(1-methyl-2-phenoxyethylamino)-1-propanol, CAS 395-28-8) is a peripheral vasodilator that also stimulates beta-adrenergic receptors. It causes a direct relaxation of vascular and uterine smooth muscles and produces positive inotropic and chronotropic effects. It is widely used to arrest premature labour and miscarriage. The aim of this trial was to investigate the pharmacokinetics of isoxsuprine hydrochloride administered orally to healthy young female volunteers as an extended-release formulation at the doses of 30, 60 and 90 mg compared to 10 mg by i.m. route. A randomised, crossover, four-period, multisequence, single-dose design was adopted. Plasma and urine concentrations of free and total isoxsuprine were evaluated by tandem mass spectrometry that reached a low quantification limit of 1 ng/ml. From plasma concentrations Cmax, tmax, AUC(0-t), AUC(0-infinity), t1/2 and Vd and from urine concentration CUE(0-24h) were evaluated by the non-compartmental model. The free drug was present only in plasma after i.m. route, whereas total isoxsuprine, namely the drug after an enzymatic hydrolysis of the conjugate form, was detected in all plasma and urine samples. The distribution volume of the free drug proved to be 2.5 times higher than that of total isoxsuprine, which indicates a good penetration of the free drug into tissue compartments. Oral absorption was evaluated from the p.o./i.m. percentualized ratio of AUC and CUE and proved to be on average around 51%, being linearly correlated with the three doses administered. The oral absorption proved to be sustained as expected from the zero-order kinetics of the drug release from the core of the extended-release formulation. This has justified different values of half-life that was on average 2.2 h after the i.m. route and around 10 h after the three oral doses. After isoxsuprine administration, both oral and i.m. routes, the heart rate increased from baseline during the 9 h monitoring period. This was an expected finding attributable to the stimulating activity of beta-adrenergic receptors. The tolerability of isoxsuprine proved to be very good with all the four administrations performed.
异克舒令（1-(4-羟苯基)-2-(1-甲基-2-苯氧基乙氨基)-1-丙醇，CAS 395-28-8）是一种外周血管扩张剂，也能刺激β-肾上腺素能受体。它可直接松弛血管和子宫平滑肌，并产生正性肌力和变时性作用。它被广泛用于阻止早产和流产。本试验的目的是研究口服盐酸异克舒令缓释制剂，以30、60和90毫克的剂量给药于健康年轻女性志愿者时的药代动力学，并与肌肉注射10毫克的情况进行比较。采用了随机、交叉、四周期、多序列、单剂量设计。通过串联质谱法评估游离和总异克舒令的血浆和尿液浓度，其低定量限达到1纳克/毫升。根据血浆浓度评估Cmax、tmax、AUC(0-t)、AUC(0-∞)、t1/2和Vd，根据尿液浓度评估CUE(0-24h)，采用非房室模型。肌肉注射后，游离药物仅存在于血浆中，而在所有血浆和尿液样本中均检测到总异克舒令，即共轭形式经酶水解后的药物。游离药物的分布容积被证明比总异克舒令高2.5倍，这表明游离药物对组织隔室有良好的渗透。通过AUC和CUE的口服/肌肉注射百分比化比值评估口服吸收情况，结果证明平均约为51%，与给药的三个剂量呈线性相关。正如从缓释制剂核心药物释放的零级动力学所预期的那样，口服吸收被证明是持续的。这解释了半衰期的不同值，肌肉注射后平均为2.2小时，三个口服剂量后约为10小时。给予异克舒令后，无论是口服还是肌肉注射途径，在9小时监测期内心率均从基线上升。这是一个预期的发现，归因于β-肾上腺素能受体的刺激活性。在进行的所有四种给药中，异克舒令的耐受性都非常好。
