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.