Pharmacokinetics and metabolism of neurotensin in man.

Abstract

We studied the pharmacokinetics, arteriovenous extraction, and degradation sites of neurotensin (NT) in man during iv infusions of synthetic intact NT [NT-(1-13)] and the NH2-terminal metabolite NT-(1-8) during lipid ingestion and by catheterization of various vascular beds in normal subjects and patients with hepatic disease. NT-like immunoreactivities in plasma were quantitated using 2 sequence-specific RIAs and gel filtration chromatography. During iv infusion of NT-(1-13) in 6 normal subjects, the median t1/2 was 1.7 min (interquartile range, 0.7-2.8), the MCR was 36 mL/kg.min (range, 21-54), and distribution space was 78.8 mL/kg (range, 56-91). The results were similar at infusion rates of 72, 144, and 288 pmol/kg.h (n = 6). During infusion of NT-(1-8) in 7 normal subjects, the median t1/2 was 8.3 min (range, 4.7-13.8), the MCR was 11.0 mL/kg.min (range, 6.7-21.7), and the distribution space was 142.6 mL/kg (range, 45.3-281.0). Significant peripheral arteriovenous extraction of NT-(1-13) was found at infusion rates of 144 and 288 pmol/kg.h. Extraction of NH2-terminal immunoreactivity was not significant. Intact NT was identified by gel chromatography in arterial plasma after lipid ingestion and iv infusion of NT-(1-13), but postprandially in only low concentrations. In 17 patients with various nonhepatic diseases, plasma intact NT levels were not different in blood sampled from the renal vein, inferior vena cava, brachial artery, or hepatic vein. In contrast, NH2-terminal immunoreactivity was significantly higher in hepatic venous than in systemic plasma. In 6 patients with hepatic disease, systemic plasma intact NT levels were increased, but even more so in hepatic venous plasma. These results demonstrate that metabolism of intact NT is rapid, and a significant peripheral arterio-venous extraction is present. Further studies are necessary to establish if the liver is a site of degradation of intact NT in man.