Influence of the Duffy antigen on pharmacokinetics and pharmacodynamics of recombinant monocyte chemoattractant protein (MCP-1, CCL-2) in vivo.
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.
Mayr
F B
FB
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Spiel
A O
AO
Leitner
J M
JM
Firbas
C
C
Schnee
J
J
Hilbert
J
J
Derendorf
H
H
Jilma
B
B
D000293:Adolescent; D000328:Adult; D001688:Biological Products / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology; D002452:Cell Count; D018932:Chemokine CCL2 / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004311:Double-Blind Method; D004375:Duffy Blood-Group System / Q000235:genetics / Q000276:immunology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology; D005838:Genotype; D006801:Humans; D007262:Infusions, Intravenous; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D055815:Young Adult
C473745:ACKR1 protein, human; D001688:Biological Products; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004375:Duffy Blood-Group System; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins