Johnston Thomas P, Kuchimanchi Kamesh R, Alur Hemant, Chittchang Montakarn, Mitra Ashim K
Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri, Kansas City, MO 64110-2499, USA.
J Pharm Pharmacol. 2003 Aug;55(8):1083-90. doi: 10.1211/0022357021530.
The aim of our study was to induce changes in the plasma elimination half-life (t(1/2)(elim)), rate and extent of urinary excretion, and biodistribution of a model macromolecule, poly-L-lysine, in rats following complexation with heparin. Male Sprague-Dawley rats were dosed intravenously with either unfractionated [(3)H]heparin, FITC-labelled poly-L-lysine, or an [(3)H]heparin:FITC-labelled poly-L-lysine complex. Serum and blood concentration vs time and urinary excretion profiles were determined as well as the resulting patterns of biodistribution to liver, spleen, kidney, and muscle tissue. While the mean values for the total body clearance of poly-L-lysine and the complex were not significantly different, the volume of distribution and the half-life associated with elimination from the serum were increased greater than 2-fold for the complex compared with free poly-L-lysine. The rate and extent of elimination in the urine followed the relative rank order; heparin > poly-L-lysine> heparin:poly-L-lysine complex. Thirty minutes following intravenous administration, there was significantly more tissue deposition/uptake of the complex in the liver, kidney, and muscle, but not the spleen, when compared with poly-L-lysine administered alone. Complexation of heparin to poly-L-lysine effectively increased the fraction of an administered dose of poly-L-lysine that was deposited in liver, kidney, and muscle tissue. Due to the macromolecular complex being nontoxic and uncharged, potentially it might serve as a suitable carrier for both conventional and peptidic drugs to increase drug distribution to liver, kidney, or muscle tissue.
我们研究的目的是在大鼠体内，观察与肝素络合后，模型大分子聚-L-赖氨酸的血浆消除半衰期（t(1/2)(elim)）、尿排泄速率和程度以及生物分布的变化。将雄性Sprague-Dawley大鼠静脉注射未分级的[(3)H]肝素、FITC标记的聚-L-赖氨酸或[(3)H]肝素:FITC标记的聚-L-赖氨酸复合物。测定血清和血液浓度随时间的变化以及尿排泄情况，以及其在肝、脾、肾和肌肉组织中的生物分布模式。虽然聚-L-赖氨酸和复合物的全身清除率平均值没有显著差异，但与游离聚-L-赖氨酸相比，复合物的分布容积和血清消除半衰期增加了2倍以上。尿中消除速率和程度的相对顺序为：肝素>聚-L-赖氨酸>肝素:聚-L-赖氨酸复合物。静脉给药30分钟后，与单独给予聚-L-赖氨酸相比，复合物在肝、肾和肌肉中的组织沉积/摄取显著增加，但在脾中没有。肝素与聚-L-赖氨酸的络合有效地增加了聚-L-赖氨酸给药剂量中沉积在肝、肾和肌肉组织中的比例。由于大分子复合物无毒且不带电荷，它有可能作为传统药物和肽类药物的合适载体，以增加药物在肝、肾或肌肉组织中的分布。
