Ghrelin levels fluctuate rapidly and dynamically with surges before mealtimes and post-prandial troughs, and ghrelin increases appetite and food intake. Circulating ghrelin correlates negatively with body mass index, but obese individuals have a reduced post-prandial decrease in ghrelin levels. Whether this reflects changes in secretion or clearance of ghrelin is uncertain. We therefore studied the pharmacokinetics of ghrelin in relation to anthropometric and biochemical measures. We also studied the effects of ghrelin on hormones and metabolites. In fasting humans, we used a constant infusion rate of ghrelin lasting 180 minutes at 5 pmol/kg body weight pr. minute to in a randomized, double-blind, placebo-controlled cross-over study. Serum ghrelin (total levels) were distributed and eliminated according to a two-compartment model. S-ghrelin initial half-life was 24+/-2 minutes and terminal half-life 146+/-36 minutes, respectively. Mean residence time (MRT) of ghrelin was 93+/-16 minutes. MRT correlated positively with both body mass index (BMI) (r=0.51, P<0.001) and high-density cholesterol (HDL) levels (r=0.75, P<0.001). Serum insulin levels remained constant during ghrelin infusion whereas plasma glucose increased 0.3+/-0.1 mmol/l (P<0.01) and free fatty acid levels more than doubled (to 1.03+/-0.08 mmol/l, P<0.001) translating into a significant reduction of insulin sensitivity (P<0.001.) In conclusion, 1) we describe novel pharmacokinetics of ghrelin useful when tailoring ghrelin infusion rates in clinical experiments, 2) BMI and HDL correlate positively with MRT of infused ghrelin, and 3) supraphysiological ghrelin levels impair insulin sensitivity.