Kikura Mutsuhito, Morita Koji, Sato Shigehito
Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, 431-3192, Hamamatsu, Japan.
Pharmacol Res. 2004 Mar;49(3):275-81. doi: 10.1016/j.phrs.2003.09.012.
Colforsin daropate, a water-soluble forskolin derivative, is an adenyl cyclase activator with positive inotropic and vasodilatory effects that are useful in the treatment of ventricular dysfunction. We investigated the pharmacokinetics of colforsin daropate in cardiac surgery patients and performed simulations to determine the dosage necessary to maintain an effective plasma concentration following cardiopulmonary bypass. In six patients undergoing coronary artery bypass graft, colforsin daropate (0.01mgkg(-1)) was administered immediately after separation from cardiopulmonary bypass. Arterial blood was sampled over the next 16h and plasma concentrations of colforsin daropate and its initial active metabolite were determined by gas-chromatography. Extended nonlinear least-squares regression was used to fit a three-compartment model to each patient's data. Distribution half-life (t(1/2alpha)) was 3.9+/-1.1min, metabolic half-life (t(1/2beta)) was 1.9+/-0.7h, and elimination half-life (t(1/2gamma)) was 95.3+/-15.2h. Central-compartment volume was 591.0+/-42.8mlkg(-1), volume distribution was 2689.2+/-450.6mlkg(-1), and elimination clearance was 27.7+/-14.7mlkg(-1)min(-1). In the pharmacokinetic simulation model, 0.5, 0.75, and 1.0microgkg(-1)min(-1) continuous infusion of colforsin daropate produce effective concentration (5-10ngml(-1)) within 30, 20, and 10min, respectively following administration. An initial active metabolite of decreased rapidly to less than 1.0ngml(-1) within the first 10min.A colforsin daropate infusion of 0.7-1.0microgkg(-1)min(-1) for 10-20min followed by 0.5microgkg(-1)min(-1) continuous infusion is recommended to produce an effective concentration (5-10ngml(-1)) within 10-20min and to maintain a therapeutic concentration throughout the administration period after cardiopulmonary bypass.
科福新达罗帕酯是一种水溶性福斯高林衍生物，是一种腺苷酸环化酶激活剂，具有正性肌力和血管舒张作用，可用于治疗心室功能障碍。我们研究了科福新达罗帕酯在心脏手术患者中的药代动力学，并进行了模拟以确定体外循环后维持有效血浆浓度所需的剂量。在6例接受冠状动脉搭桥术的患者中，科福新达罗帕酯（0.01mg/kg(-1)）在体外循环结束后立即给药。在接下来的16小时内采集动脉血，通过气相色谱法测定科福新达罗帕酯及其初始活性代谢物的血浆浓度。采用扩展非线性最小二乘回归法对每位患者的数据拟合三室模型。分布半衰期（t(1/2α)）为3.9±1.1分钟，代谢半衰期（t(1/2β)）为1.9±0.7小时，消除半衰期（t(1/2γ)）为95.3±15.2小时。中央室容积为591.0±42.8ml/kg(-1)，分布容积为2689.2±450.6ml/kg(-1)，消除清除率为27.7±14.7ml/kg(-1)min(-1)。在药代动力学模拟模型中，分别在给药后30、20和10分钟内，以0.5、0.75和1.0μg/kg(-1)min(-1)的速率持续输注科福新达罗帕酯可产生有效浓度（5-10ng/ml）。初始活性代谢物在最初10分钟内迅速降至1.0ng/ml以下。建议先以0.7-1.0μg/kg(-1)min(-1)的速率输注科福新达罗帕酯10-20分钟，然后以0.5μg/kg(-1)min(-1)的速率持续输注，以便在10-20分钟内产生有效浓度（5-10ng/ml），并在体外循环后的整个给药期间维持治疗浓度。
