Pharmacokinetics and organ-specific metabolism of calcitonin gene-related peptide in sheep.
Calcitonin gene-related peptide (CGRP) is a product of the calcitonin gene with a widespread distribution in neural tissue of the brain, gut and perivascular nerves. Infusion of CGRP produces multiple biological effects, but the physiological significance of these findings will be influenced by the sites and rates of CGRP metabolism. The metabolic clearance rate and half-life of disappearance of human CGRP were estimated in conscious sheep after infusing CGRP at 1 or 5 pmol/kg per min to steady-state conditions. The particular organs involved in the clearance of CGRP were assessed by measuring the inflow and outflow concentrations across the liver, gut, kidney, lung and brain. The metabolic clearance rate at steady state was 22.6 +/- 2.1 (S.E.M.) and 15.0 +/- 17 ml/kg per min for the 1 and 5 pmol/kg per min doses respectively. The half-life of disappearance was bi-exponential: 3.6 +/- 0.3 min for the first phase and 13.6 +/- 1.0 min for the second phase. High-pressure liquid chromatography of plasma at equilibrium revealed only a single peak coeluting with CGRP(1-37): no immunoreactive metabolites were detected. These pharmacokinetic values are intermediate between that of a neurotransmitter and a hormone and are therefore consistent for a peptide with both circulatory and neurotransmitter modes of action. The kidney, with an arterial-renal vein gradient of 14%, and the liver, with a portal-hepatic vein gradient of 25%, were the major organs involved in the clearance of CGRP.(ABSTRACT TRUNCATED AT 250 WORDS)
Braslis
K G
KG
Department of Surgery, University of Melbourne, Austin Hospital, Victoria, Australia.
Shulkes
A
A
Fletcher
D R
DR
Hardy
K J
KJ
D000818:Animals; D001921:Brain / Q000378:metabolism; D002116:Calcitonin / Q000235:genetics*; D015740:Calcitonin Gene-Related Peptide; D005260:Female; D006207:Half-Life; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008657:Metabolic Clearance Rate; D009479:Neuropeptides / Q000378:metabolism*; D012756:Sheep
D009479:Neuropeptides; D002116:Calcitonin; D015740:Calcitonin Gene-Related Peptide