Lung uptake of ¹³¹I-metaiodobenzylguanidine in sheep

Abstract

Circulating biogenic amines are known to be cleared by the mammalian lung. Their lung uptake is considered as an indicator of pulmonary endothelial integrity. Unfortunately, their use as markers of pulmonary metabolic function in human pathology is precluded by their biological effects and by the type of radiolabeling (³H and ¹⁴C), making them harmful for repeat injections and unfit for scintigraphy. Metaiodobenzylguanidine (MIBG) is structurally related to the neuron blocking agent guanethidine, devoid of significant biological effects, and has been shown to be extracted by the same active sodium dependent, saturable transport as norepinephrine in perfused rat lungs in vitro. We studied the single pass lung extraction of ¹³¹I-MIBG in five awake and five anaesthetised sheep using the standard double indicator dilution technique with ^99mTc-human serum albumin (HSA) as an intravascular reference tracer. Intravenous bolus injection of increasing doses of MIBG up to 400 nmol resulted in a significant (F ratio=7.778, P<0.0001) dose dependent decrease of MIBG extraction in both awake and anaesthetised sheep, without significant differences of extraction values between the two groups. For the 10 sheep, the averaged percentage single pass pulmonary uptake of MIBG at the peak of the dilution curve decreased from 32%±3% (mean±SE, n=27 measurements) with 20 nmol to 18%±2% (n=32) with 400 nmol. Estimates of the apparent Michaelis-Menten constant (K _m) averaged 2±1.2 μM (n=7), whereas estimates of the apparent maximum velocity of removal (V _max) was 1.1±0.5 μmol/min (n=7). In contrast to some intersubject variability, the pharmacokinetic parameters showed little intra subject variation. No correlation was found between MIBG extraction, K _m or V _max values and haemodynamic or gas exchange parameters. These data indicate that using a standard double dilution technique, lung extraction of MIBG may be determined in vivo. Its lung removal is dose limited and may be characterised by the Michaelis-Menten kinetic constants suggesting a saturable process. In contrast to norepinephrine, the gamma emitter labeled MIBG could therefore be a suitable compound to monitor pulmonary endothelial cell function in vivo using a non invasive scintigraphic method.