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Leptin is an adipocyte-secreted hormone that regulates energy homeostasis and neuroendocrine function. Replacement therapy with recombinant methionyl human leptin (r-metHuLeptin) improves obesity, insulin resistance, hyperlipidemia, and neuroendocrine dysfunction associated with low-leptin states. We administered three doses of r-metHuLeptin (0.1, 0.3, and 1.0 mg/kg) to healthy subjects to determine r-metHuLeptin pharmacokinetics in the fed state, to determine endogenous leptin production and clearance rates, and to study the effects of age, body mass index, gender, and race on r-metHuLeptin pharmacokinetics. We detected no dose-dependent effects on elimination half-life (t(1/2)), dose-normalized area under the curve (nAUC(0- infinity)), total body clearance (CL), or volume of distribution at steady state. The mean t(1/2), CL, and volume of distribution at steady state of r-metHuLeptin are 3.4 +/- 1.5 h, 79 +/- 16 ml/kg.h, and 150 +/- 39 ml/kg, respectively. Older subjects have a higher nAUC(0- infinity) (P = 0.003) and tend to have a decreased leptin production rate (Rsyn) and CL (P = 0.01). Increased body mass index is associated with higher baseline endogenous leptin levels (P &lt; 0.0001), higher Rsyn (P &lt; 0.0001), and longer t(1/2) (P = 0.008). Females have significantly greater baseline endogenous leptin levels and Rsyn than males (P &lt; 0.0001). In summary, the leptin production rate is increased in females and with increasing adiposity, whereas leptin clearance is decreased with increasing adiposity, and nAUC(0- infinity) is increased with age. Elucidation of leptin pharmacokinetic parameters allows the accurate calculation of exogenous leptin replacement doses for humans in the fed state.

Leptin Hormonal Kinetics in the Fed State: Effects of Adiposity, Age, and Gender on Endogenous Leptin Production and Clearance Rates