The biodistribution, pharmacokinetics and multi-organ clearance of the vasodilator peptide AM (adrenomedullin) were evaluated in rats and its single-pass pulmonary clearance was measured in dogs by the indicator-dilution technique. Intravenously administered 125I-rAM(1–50) [rat AM(1–50)] was rapidly cleared following a two-compartment model with a very rapid distribution half-life of 2.0 min [95% CI (confidence interval), 1.98–2.01] and an elimination half-life of 15.9 min (95% CI, 15.0–16.9). The lungs retained most of the injected activity with evidence of single-pass clearance, since retention was lower after intra-arterial (13.5±0.6%) compared with intravenous (30.4±1.5%; P<0.001) injection. Lung tissue levels of total endogenous AM were 20-fold higher than in other organs with no difference in plasma levels across the pulmonary circulation. In dogs, there was 36.4±2.1% first-pass unidirectional extraction of 125I-rAM(1–50) by the lungs that was reduced to 21.9±2.4% after the administration of unlabelled rAM(1–50) (P<0.01). Extraction was not affected by calcitonin-gene-related peptide administration (40.6±2.9%), but was slightly reduced by the C-terminal fragment of human AM(22–52) (31.4±3.3%; P<0.01). These data demonstrate that the lungs are a primary site for AM clearance in vivo with approx. 36% first-pass extraction through specific receptors. This suggests that the lungs not only modulate circulating levels of this peptide, but also represent its primary target.
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Research Article|
June 23 2005
Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin
Jocelyn DUPUIS;
1Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
Correspondence: Dr Jocelyn Dupuis (email [email protected]).
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Alexandre CARON;
Alexandre CARON
1Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
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Nathalie RUËL
Nathalie RUËL
1Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
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Publisher: Portland Press Ltd
Received:
December 13 2004
Revision Received:
February 17 2005
Accepted:
March 01 2005
Accepted Manuscript online:
March 01 2005
Online ISSN: 1470-8736
Print ISSN: 0143-5221
The Biochemical Society
2005
Clin Sci (Lond) (2005) 109 (1): 97–102.
Article history
Received:
December 13 2004
Revision Received:
February 17 2005
Accepted:
March 01 2005
Accepted Manuscript online:
March 01 2005
Citation
Jocelyn DUPUIS, Alexandre CARON, Nathalie RUËL; Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin. Clin Sci (Lond) 1 July 2005; 109 (1): 97–102. doi: https://doi.org/10.1042/CS20040357
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