Mayr F B, Spiel A O, Leitner J M, Firbas C, Schnee J, Hilbert J, Derendorf H, Jilma B
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Int J Immunopathol Pharmacol. 2009 Jul-Sep;22(3):615-25. doi: 10.1177/039463200902200307.
Monocyte chemoattractant protein-1 (MCP-1, CCL-2) binds to the Duffy antigen (DARC) on red blood cells, which act as a sink for several chemokines including MCP-1. In this study it is hypothesized that DARC may alter the pharmacokinetics of infused recombinant human MCP-1 (rhMCP-1). The primary aim of this first in man trial is to compare the pharmacokinetics of rhMCP-1 in Duffy positive and negative individuals. A randomized, double-blinded, placebo-controlled dose escalation trial was conducted on 36 healthy volunteers. Subjects received infusions of 0.02-2.0 microg/kg rhMCP-1 or placebo for one hour. RhMCP-1 displayed linear pharmacokinetics. Duffy negative individuals reached maximal plasma levels significantly earlier, but overall plasma concentration profiles were not altered. rhMCP-1 markedly increased monocyte counts, and estimated EC50 values were 10-fold higher in Duffy positive than in Duffy negative subjects. Increased monocyte counts were associated with decreased surface expression of intercellular adhesion molecule 1 (ICAM-1, CD54). In contrast, neither CCR-2 or CD11b expression, nor markers of platelet or endothelial activation, inflammation and coagulation were altered. RhMCP-1 is a highly selective chemoattractant for monocytes in humans. The Duffy antigen only minimally alters the pharmacokinetics of rhMCP-1 for doses up to 2 microg/kg.
单核细胞趋化蛋白-1（MCP-1，CCL-2）与红细胞上的达菲抗原（DARC）结合，而达菲抗原可作为包括MCP-1在内的多种趋化因子的汇聚点。在本研究中，我们假设DARC可能会改变输注的重组人MCP-1（rhMCP-1）的药代动力学。这项首次人体试验的主要目的是比较rhMCP-1在达菲阳性和阴性个体中的药代动力学。对36名健康志愿者进行了一项随机、双盲、安慰剂对照的剂量递增试验。受试者接受0.02 - 2.0微克/千克rhMCP-1或安慰剂输注1小时。rhMCP-1呈现线性药代动力学。达菲阴性个体达到最大血浆水平的时间显著更早，但总体血浆浓度曲线未改变。rhMCP-1显著增加单核细胞计数，且达菲阳性受试者的估计半数有效浓度（EC50）值比达菲阴性受试者高10倍。单核细胞计数增加与细胞间黏附分子1（ICAM-1，CD54）的表面表达降低相关。相比之下，CCR-2或CD11b的表达，以及血小板或内皮细胞活化、炎症和凝血的标志物均未改变。RhMCP-1是一种对人类单核细胞具有高度选择性的趋化因子。对于高达2微克/千克的剂量，达菲抗原仅对rhMCP-1的药代动力学有最小程度的改变。
