Dupuis Jocelyn, Caron Alexandre, Ruël Nathalie
Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada.
Clin Sci (Lond). 2005 Jul;109(1):97-102. doi: 10.1042/CS20040357.
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.
在大鼠中评估了血管舒张肽AM（肾上腺髓质素）的生物分布、药代动力学和多器官清除率，并通过指示剂稀释技术在犬中测量了其单通道肺清除率。静脉注射125I-rAM(1-50) [大鼠AM(1-50)]后，按照二室模型迅速清除，分布半衰期非常短，为2.0分钟[95%置信区间（CI），1.98 - 2.01]，消除半衰期为15.9分钟（95% CI，15.0 - 16.9）。肺部保留了大部分注入的活性，有单通道清除的证据，因为与静脉注射（30.4±1.5%）相比，动脉内注射后保留率较低（13.5±0.6%；P < 0.001）。肺组织中内源性AM总量比其他器官高20倍，肺循环中血浆水平无差异。在犬中，肺部对125I-rAM(1-50)的首过单向提取率为36.4±2.1%，给予未标记的rAM(1-50)后降至21.9±2.4%（P < 0.01）。降钙素基因相关肽给药后提取率不受影响（40.6±2.9%），但人AM(22-52)的C末端片段使其略有降低（31.4±3.3%；P < 0.01）。这些数据表明，肺是体内AM清除的主要部位，约36%通过特异性受体进行首过提取。这表明肺不仅调节该肽的循环水平，而且是其主要靶点。
