Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin.
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.
Dupuis
Jocelyn
J
Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada. jocelyn.dupuis@bellnet.ca
Caron
Alexandre
A
Ruël
Nathalie
N
D053607:Adrenomedullin; D000818:Animals; D004285:Dogs; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D010455:Peptides / Q000097:blood / Q000493:pharmacokinetics*; D011652:Pulmonary Circulation; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014665:Vasodilator Agents / Q000097:blood / Q000493:pharmacokinetics*
D007457:Iodine Radioisotopes; D010455:Peptides; D019275:Radiopharmaceuticals; D014665:Vasodilator Agents; D053607:Adrenomedullin