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 I-125-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 I-125-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.