基于人体生理药代动力学模型对血管紧张素转换酶抑制剂:雷米普利和ramiprilat。
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莱维特DG,舒梅克RC
基于人体生理药代动力学模型对血管紧张素转换酶抑制剂:雷米普利和ramiprilat。
BMC杂志。2006年1月6日,6:1。
- PubMed ID
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16398929 (在PubMed]
- 文摘
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背景:血管紧张素转换酶(ACE)抑制剂的复杂和不佳的药物动力学特征。有两个结合位点/ ACE(高亲和力“C”,“N”)低亲和力sub-nanomolar亲和力和离解的小时。大多数抑制剂口服的药物前体形式系统转化为活性形式。介绍了第一个人类生理基础这种药类的药代动力学(PBPK)模型。方法:该模型应用于实验数据的范Griensven等人的药物动力学ramiprilat及其前体药物雷米普利。它描述了时间的N和C的抑制ACE网站在等离子体和不同的组织。该模型包括:1)两个独立的ACE结合位点;2)非平衡与时间有关的绑定;3)肝脏和肾脏雷米普利细胞内吸收,转换ramiprilat和挤压从细胞;4)肠道雷米普利吸收。 The experimental in vitro ramiprilat/ACE binding kinetics at 4 degrees C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest. RESULTS: The PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution. CONCLUSION: If the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained.