Comparison of pharmacokinetics and vasodilatory effect of nebulized and infused iloprost in experimental pulmonary hypertension: rapid tolerance development.

Ralph Theo Schermuly, Andreas Schulz, Hossein Ardeschir Ghofrani, Christina Susanne Breitenbach, Norbert Weissmann, Michael Hildebrand, Julia Kurz, Friedrich Grimminger, Werner Seeger
{"title":"Comparison of pharmacokinetics and vasodilatory effect of nebulized and infused iloprost in experimental pulmonary hypertension: rapid tolerance development.","authors":"Ralph Theo Schermuly,&nbsp;Andreas Schulz,&nbsp;Hossein Ardeschir Ghofrani,&nbsp;Christina Susanne Breitenbach,&nbsp;Norbert Weissmann,&nbsp;Michael Hildebrand,&nbsp;Julia Kurz,&nbsp;Friedrich Grimminger,&nbsp;Werner Seeger","doi":"10.1089/jam.2006.19.353","DOIUrl":null,"url":null,"abstract":"<p><p>Aerosolized iloprost has been suggested for selective pulmonary vasodilatation in severe pulmonary hypertension, but its pharmacokinetic profile is largely unknown. In perfused rabbit lungs, continuous infusion of the thromboxane mimetic U46619 was employed for establishing stable pulmonary hypertension. Delivery of a total amount of 75, 300, and 900 ng of iloprost to the bronchoalveolar space by a 10 min-aerosolization maneuver caused a dose-dependent pulmonary vasodilatation. Similarly, dose-dependent appearance of iloprost in the recirculating perfusate was noted, with maximum intravascular concentrations of iloprost ranging at 140, 510, and 1163 pg/mL at the same time period. Comparing pharmacokinetics and pharmacodynamics in a more detailed fashion, the following aspects were of interest. (i) The bioavailability (i.e., the percentage of aerosolized iloprost appearing intravascularly) decreased from 76% at the lowest to 33% at the highest iloprost dosage. (ii) The pulmonary vasodilatory response commenced already during the nebulization maneuver and preceded the perfusate entry of iloprost. (iii) After 3-3.5 h, the pulmonary vasodilatory response to aerosolized iloprost had virtually completely leveled off, whereas approximately two-thirds of the maximum iloprost perfusate levels were still detectable. A corresponding loss of vasodilatory response was also noted in experiments with continuous iloprost perfusion for clamping of the intravascular concentration of this prostanoid. We conclude that aerosolized iloprost causes dose-dependent vasodilatation and iloprost entry into the vascular space in a pulmonary hypertension model. Limited bioavailability in the higher dose range may suggest active prostanoid transport processes, and the early pulmonary vasodilatory response appears to be independent of prostanoid entry into the vessel lumen. Surprisingly, rapid tolerance development to the vasodilatory effect of iloprost is noted, occurring even with fully maintained perfusate levels of this agent.</p>","PeriodicalId":14878,"journal":{"name":"Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine","volume":"19 3","pages":"353-63"},"PeriodicalIF":0.0000,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/jam.2006.19.353","citationCount":"18","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1089/jam.2006.19.353","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 18

Abstract

Aerosolized iloprost has been suggested for selective pulmonary vasodilatation in severe pulmonary hypertension, but its pharmacokinetic profile is largely unknown. In perfused rabbit lungs, continuous infusion of the thromboxane mimetic U46619 was employed for establishing stable pulmonary hypertension. Delivery of a total amount of 75, 300, and 900 ng of iloprost to the bronchoalveolar space by a 10 min-aerosolization maneuver caused a dose-dependent pulmonary vasodilatation. Similarly, dose-dependent appearance of iloprost in the recirculating perfusate was noted, with maximum intravascular concentrations of iloprost ranging at 140, 510, and 1163 pg/mL at the same time period. Comparing pharmacokinetics and pharmacodynamics in a more detailed fashion, the following aspects were of interest. (i) The bioavailability (i.e., the percentage of aerosolized iloprost appearing intravascularly) decreased from 76% at the lowest to 33% at the highest iloprost dosage. (ii) The pulmonary vasodilatory response commenced already during the nebulization maneuver and preceded the perfusate entry of iloprost. (iii) After 3-3.5 h, the pulmonary vasodilatory response to aerosolized iloprost had virtually completely leveled off, whereas approximately two-thirds of the maximum iloprost perfusate levels were still detectable. A corresponding loss of vasodilatory response was also noted in experiments with continuous iloprost perfusion for clamping of the intravascular concentration of this prostanoid. We conclude that aerosolized iloprost causes dose-dependent vasodilatation and iloprost entry into the vascular space in a pulmonary hypertension model. Limited bioavailability in the higher dose range may suggest active prostanoid transport processes, and the early pulmonary vasodilatory response appears to be independent of prostanoid entry into the vessel lumen. Surprisingly, rapid tolerance development to the vasodilatory effect of iloprost is noted, occurring even with fully maintained perfusate levels of this agent.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
伊洛前列素雾化与输注治疗实验性肺动脉高压的药代动力学及血管舒张作用比较:快速耐受性发展。
雾化伊洛前列素已被建议用于严重肺动脉高压患者的选择性肺血管扩张,但其药代动力学特征在很大程度上是未知的。在灌注兔肺中,连续输注模拟血栓素U46619建立稳定的肺动脉高压。通过10分钟雾化操作将伊洛前列素总剂量分别为75、300和900 ng至支气管肺泡间隙引起剂量依赖性肺血管舒张。同样,伊洛前列素在循环灌注液中的剂量依赖性表现也被注意到,在同一时间段内,伊洛前列素的最大血管内浓度范围为140、510和1163 pg/mL。比较药代动力学和药效学在更详细的方式,以下方面是感兴趣的。(i)生物利用度(即伊洛前列素雾化出现在血管内的百分比)从最低剂量的76%下降到最高剂量的33%。(ii)肺血管扩张反应在雾化操作期间已经开始,在伊洛前列素进入灌注之前。(iii)在3-3.5小时后,雾化伊洛前列素的肺血管扩张反应几乎完全趋于平稳,而仍可检测到约三分之二的最大伊洛前列素灌注水平。在持续灌注伊洛前列素以抑制血管内这种前列腺素浓度的实验中,也注意到相应的血管舒张反应的丧失。我们得出结论,在肺动脉高压模型中,雾化伊洛前列素引起剂量依赖性血管扩张和伊洛前列素进入血管间隙。高剂量范围内有限的生物利用度可能提示活跃的前列腺素转运过程,早期肺血管舒张反应似乎与前列腺素进入血管腔无关。令人惊讶的是,对伊洛前列素血管扩张作用的快速耐受性发展被注意到,即使在完全维持该药物灌注水平的情况下也会发生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Formoterol turbuhaler is as effective as salbutamol diskus in relieving adenosine-induced bronchoconstriction in children. An in vitro study to assess facial and ocular deposition from Respimat Soft Mist inhaler. Exhaled breath condensate pH is increased after moderate exercise. The analysis and prediction of functional robustness of inhaler devices. Comparison of the Diskus inhaler and the Handihaler regarding preference and ease of use.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1