Stevens A J, Martin S W, Brennan B S, McLachlan A, Gifford L A, Rowland M, Houston J B
Department of Pharmacy, University of Manchester, United Kingdom.
Pharm Res. 1995 Dec;12(12):1987-96. doi: 10.1023/a:1016212510900.
To quantify the advantage gained by direct administration to a target site for two non-steroidal anti-inflammatory drugs (NSAIDs) piroxicam and diclofenac in the rat air pouch model of inflammation. To derive a model relating drug targeting index (DTI) to the pharmacokinetic parameters of the target and systemic sites, and to compare predictions with observations.
DTI was calculated based on area under the concentration time curve at target (pouch) and systemic site (venous blood) following administration into and sampling from both sites. A model was derived relating DTI to systemic clearance, target permeability, plasma protein binding and fraction of the targeted dose that is systemically available.
Both NSAIDs exhibited linear pharmacokinetics over the dose ranges studies. They differed primarily in total body clearance which was approximately 16 fold greater for diclofenac (213 ml hr-1 per 250 g) than piroxicam (13 ml hr-1 per 250 g). Observed DTIs (11, 114 and 276 for piroxicam, S[+]ibuprofen [studied previously] and diclofenac) were ranked in order of total body clearance but were approximately 7.5 fold lower than predicted (101, 700 and 2214 respectively).
The discrepancy was explained by the influx of the plasma binding protein, albumin, into the target site due to increased vascular permeability associated with the inflammatory response. The originally derived equation for DTI, which assumed only unbound drug diffuses across the target site, was modified to take into account the simultaneous flux of bound drug.
在大鼠气囊炎症模型中，量化两种非甾体抗炎药（NSAIDs）吡罗昔康和双氯芬酸直接给药至靶部位所获得的优势。推导一个将药物靶向指数（DTI）与靶部位和全身部位的药代动力学参数相关联的模型，并将预测结果与观察结果进行比较。
根据给药至靶部位（气囊）和全身部位（静脉血）并从这两个部位采样后，靶部位（气囊）和全身部位（静脉血）浓度 - 时间曲线下面积计算DTI。推导一个将DTI与全身清除率、靶部位通透性、血浆蛋白结合率以及全身可利用的靶向剂量分数相关联的模型。
在研究的剂量范围内，两种NSAIDs均表现出线性药代动力学。它们的主要差异在于总体清除率，双氯芬酸（每250 g为213 ml·hr⁻¹）的总体清除率比吡罗昔康（每250 g为13 ml·hr⁻¹）大约高16倍。观察到的DTI（吡罗昔康、[先前研究的] S（+）布洛芬和双氯芬酸分别为11、114和276）按总体清除率排序，但比预测值（分别为101、700和2214）低约7.5倍。
差异的原因是与炎症反应相关的血管通透性增加，导致血浆结合蛋白白蛋白流入靶部位。最初推导的DTI方程仅假设未结合药物扩散穿过靶部位，现进行了修改以考虑结合药物的同时通量。
