Bachert E L, Li Z W, Zhao L, Chung S J, Fung H L
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo 14260.
Pharm Res. 1994 Aug;11(8):1190-8. doi: 10.1023/a:1018953319288.
Nicorandil, a vasodilator which acts through both cyclic GMP accumulation and K+ channel opening, has been used in the treatment of various cardiovascular diseases. We have examined the pharmacokinetics of nicorandil in the rat as a function of dose, as both i.v. boluses (9 doses, 0.75-12 mg, n = 1.4 per dose), and as a 5-hr infusion followed by a 5-hr washout (6 doses, 10-500 micrograms/kg/min, n = 3 per dose). Plasma nicorandil concentrations were determined by HPLC. Nicorandil plasma concentrations increased disproportionately with dose, but nicorandil elimination obeyed apparent monoexponential kinetics, and the apparent half-life (t1/2) increased with dose. In addition, the approach to apparent steady-state during the infusion phase was not overtly sensitive to the drastic changes in t1/2 observed. Pharmacokinetic modelling with several nonlinear models, viz: Michaelis-Menten with parallel first-order, cosubstrate depletion and competitive product inhibition, were carried out. Addition of the sulfhydryl donor, N-acetyl-L-cysteine, did not change the pharmacokinetics of nicorandil, providing experimental indication that a cosubstrate depletion model might not be applicable. To described the unique pharmacokinetics, a modified product inhibition model was developed. This new model includes the classic competitive product inhibition equation, describing both parent and product kinetics, and it incorporates, in addition, separate first-order elimination rate constants for both nicorandil and the inhibition metabolite. Experimental evidence showed that N-(2-hydroxyethyl) nicotinamide, the major metabolite of nicorandil in rats, and nicotinamide (niacinamide) itself, indeed inhibited nicorandil elimination.
尼可地尔是一种通过环鸟苷酸（cGMP）蓄积和钾离子通道开放发挥作用的血管扩张剂，已用于治疗多种心血管疾病。我们研究了尼可地尔在大鼠体内的药代动力学与剂量的关系，包括静脉推注（9个剂量，0.75 - 12毫克，每个剂量n = 14）以及5小时输注后接着5小时洗脱期（6个剂量，10 - 500微克/千克/分钟，每个剂量n = 3）。通过高效液相色谱法（HPLC）测定血浆尼可地尔浓度。尼可地尔血浆浓度随剂量不成比例增加，但尼可地尔消除遵循表观单指数动力学，且表观半衰期（t1/2）随剂量增加。此外，输注阶段达到表观稳态的过程对观察到的t1/2的剧烈变化并不明显敏感。使用几种非线性模型进行药代动力学建模，即：具有平行一级反应、共底物耗竭和竞争性产物抑制的米氏方程。添加巯基供体N - 乙酰 - L - 半胱氨酸并未改变尼可地尔的药代动力学，这提供了实验证据表明共底物耗竭模型可能不适用。为描述独特的药代动力学，开发了一种改进的产物抑制模型。这个新模型包括经典的竞争性产物抑制方程，描述母体和产物动力学，此外还纳入了尼可地尔及其抑制性代谢物各自的一级消除速率常数。实验证据表明，尼可地尔在大鼠体内的主要代谢产物N - （2 - 羟乙基）烟酰胺以及烟酰胺本身确实抑制尼可地尔的消除。
