Straehl P, Galeazzi R L
Clin Pharmacol Ther. 1985 Aug;38(2):140-9. doi: 10.1038/clpt.1985.150.
We studied the kinetics of isosorbide dinitrate (ISDN) after a dose of 5 mg iv and the bioavailability of a sublingual and an oral preparation of ISDN. Plasma levels of isosorbide 5-mononitrate (IS-5-MN), isosorbide 2-mononitrate (IS-2-MN), and ISDN were determined by GLC. After intravenous and sublingual dosing, ISDN plasma levels declined biexponentially and could adequately be described by an open two-compartment body model. Distribution was rapid; the t1/2 was 4.7 minutes after intravenous injection and 8.7 minutes after sublingual dosing. The volume of distribution at steady state was 90 L. The terminal disappearance t1/2 was 54.7 minutes after intravenous injection, 48.8 minutes after sublingual dosing, and 47.7 minutes after oral dosing. Total plasma clearance was 136 L/hr, exceeding normal liver plasma flow and indicating extrahepatic metabolism of ISDN. ISDN bioavailability after oral (10 mg) or sublingual dosing (10 mg) was similar (about 29%), indicating that the first-pass effect cannot be avoided by sublingual ISDN dosing. After intravenous ISDN, mononitrate plasma levels could be adequately described by another two-compartment body model. The terminal t1/2 was 4.33 hours for IS-5-MN and 1.83 hours for IS-2-MN. Noncompartmental calculations of the mononitrate levels revealed 100% systemic availability after oral and sublingual ISDN. We assume that ISDN was completely absorbed from the gastrointestinal tract, but 70% was metabolized during the first pass through the liver. After 5 mg iv ISDN, 16 mumol IS-5-MN and 5.3 mumol IS-2-MN reached systemic circulation. The entire dose of ISDN was converted to its two metabolites in a ratio of 3:1 (i.e., 75% IS-5-MN and 25% IS-2-MN).
我们研究了静脉注射5毫克剂量的硝酸异山梨酯（ISDN）后的动力学以及ISDN舌下制剂和口服制剂的生物利用度。采用气相色谱法（GLC）测定了5-单硝酸异山梨酯（IS-5-MN）、2-单硝酸异山梨酯（IS-2-MN）和ISDN的血浆水平。静脉注射和舌下给药后，ISDN血浆水平呈双指数下降，可用开放二室模型充分描述。分布迅速；静脉注射后t1/2为4.7分钟，舌下给药后为8.7分钟。稳态分布容积为90升。静脉注射后终末消除t1/2为54.7分钟，舌下给药后为48.8分钟，口服给药后为47.7分钟。总血浆清除率为136升/小时，超过正常肝血浆流量，并表明ISDN存在肝外代谢。口服（10毫克）或舌下给药（10毫克）后ISDN的生物利用度相似（约29%），表明舌下含服ISDN不能避免首过效应。静脉注射ISDN后，单硝酸酯血浆水平可用另一个二室模型充分描述。IS-5-MN的终末t1/2为4.33小时，IS-2-MN为1.83小时。单硝酸酯水平的非房室计算显示口服和舌下含服ISDN后全身利用率为100%。我们假设ISDN从胃肠道完全吸收，但70%在首次通过肝脏时被代谢。静脉注射5毫克ISDN后，16微摩尔IS-5-MN和5.3微摩尔IS-2-MN进入体循环。ISDN的整个剂量以3:1的比例转化为其两种代谢产物（即75%为IS-5-MN，25%为IS-2-MN）。
