Avram Michael J, Henthorn Thomas K, Spyker Daniel A, Krejcie Tom C, Lloyd Peter M, Cassella James V, Rabinowitz Joshua D
Department of Anesthesiology and Mary Beth Donnelley Clinical Pharmacology Core Facility, Northwestern University Feinberg School of Medicine, Chicago, IL 60611-3008, USA.
Drug Metab Dispos. 2007 Feb;35(2):262-7. doi: 10.1124/dmd.106.010652. Epub 2006 Nov 1.
A thermal aerosol generation process is capable of delivering pure drug reliably to the alveoli where it is absorbed systemically. Although deep lung absorption of drugs administered as an aerosol has been shown to be rapid, detailed characterization of their absorption and distribution has not been reported. The present study describes the pharmacokinetics of prochlorperazine from the moment of administration as either a rapid intravenous infusion or a thermally generated aerosol and determines the bioavailability of the aerosol by two independent methods. Prochlorperazine disposition was determined in four anesthetized dogs after a 5-s intravenous infusion and after thermally generated aerosol administration in one breath. Venous blood samples were collected frequently from the time of drug administration to 24 h and left ventricular blood samples were drawn more often until 10 min after drug administration. Prochlorperazine disposition after intravenous and aerosol administration was characterized by fitting a recirculatory model to left ventricular and venous drug concentration data simultaneously. Prochlorperazine aerosol administration produced plasma drug concentrations similar to those after rapid intravenous administration of the same nominal dose, with peak left ventricular concentrations achieved in less than 30 s. Plasma concentration profiles of prochlorperazine administered by both routes were well described by the recirculatory model. Bioavailability of the thermally generated aerosol was consistent and averaged more than 80% of emitted dose. Pulmonary administration of a thermally generated drug aerosol in one breath may be a viable alternative to rapid intravenous administration of drugs requiring rapid and predictable production of effective plasma concentrations.
热气溶胶生成过程能够将纯药物可靠地输送到肺泡，药物在肺泡中被全身吸收。尽管已证明以气雾剂形式给药的药物在肺部深处的吸收很快，但尚未有关于其吸收和分布的详细特征报道。本研究描述了从快速静脉输注或热生成气雾剂给药时刻起的氯丙嗪药代动力学，并通过两种独立方法确定了气雾剂的生物利用度。在四只麻醉犬中，分别在进行5秒静脉输注后以及一次呼吸内给予热生成气雾剂后，测定氯丙嗪的处置情况。从给药时刻起至24小时频繁采集静脉血样，在给药后10分钟内更频繁地采集左心室血样。通过将循环模型同时拟合到左心室和静脉药物浓度数据，来表征静脉注射和气雾剂给药后氯丙嗪的处置情况。氯丙嗪气雾剂给药产生的血浆药物浓度与相同标称剂量快速静脉给药后的浓度相似，在不到30秒内达到左心室峰值浓度。两种给药途径的氯丙嗪血浆浓度曲线均能被循环模型很好地描述。热生成气雾剂的生物利用度一致，平均超过发射剂量的80%。一次呼吸内给予热生成药物气雾剂进行肺部给药，对于需要快速且可预测地产生有效血浆浓度的药物而言，可能是快速静脉给药的一种可行替代方法。
