Development of a new method for bioavailability assessment using a pharmacokineic/pharmacodynamic model

多肽制备的自动化合成和重组DNA方法的快速发展使各种具有潜在治疗价值的多肽和多肽类似物成为可能。例如合成的多肽激素(如胰岛素、加压素、降钙素、生长抑素等)、多肽类似物、肾素抑制剂和血管紧张素转换酶抑制剂目前可用于临床。这些化合物通常的给药途径是血管内、肌肉内或皮下；然而，已有一些关于注射引起的副作用的报道。尽管口服、直肠或鼻腔给药已引起广泛关注，但由于其可能改善副作用，这些药物在血管外给药后的生物利用度评估是极其困难的。本项目的目标是开发一种新的生物利用度评价方法，并优化这些药物的口服和鼻腔给药方案。以卡托普利(CP)、鲑鱼降钙素(SCT)和精氨酸加压素(AVP)为模型化合物。建立了包括动脉压调节系统、血钙调节系统和/或尿钠调节系统等生理调节系统的药代动力学(PK)/药效学(PD)模型，并对这些药物血管外给药后的药理数据进行了分析。结果表明，PK/PD模型能较准确地估计药物的生物利用度和生物利用度。

The rapid development of automated synthetic and recombinant DNA methods of peptide preparation have made available a great variety of peptide and peptide analogs of potential therapeutic value. Example include synthetic peptide hormons (such as insulin, vasopressin, calcitonin, somatostatin, etc.), peptide analogs, renin inhibitors, and angiotensin converting enzyme inhibitors are currently available for clinical use. The usual route of adsministration of these compounds were intravascular, intramuscular or subcutaneous ; however, a number of side effects due to injection have been reported. Although, oral, rectal or nasal route have attracted ateension, because of its potential to improve the side-effects, the assesment of bioavailability after extravascular administration of these drugs are extremely difficult. The objective of this project is to develop a new method for bioavailability assessment and to optimise the dosage regimens after oral nasal administration of these drugs. Captopril (CP), salmon calcitonin (sCT) and arginine vasopressin (AVP) were used as model compounds. A pharmacokinetic (PK) / pharmacodynamic (PD) model, including physiological regulation systems, such as arterial pressure control system, plasma calcium regulation system and/or urinary sodium regulation system was constructued, and the pharmacological data after extravascular administraiton of these drugs were analyzed. Results indicated that the rate and extent of bioavailability of these drugs were precisely estimated by the PK/PD model.