Leptin hormonal kinetics in the fed state: effects of adiposity, age, and gender on endogenous leptin production and clearance rates.
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 < 0.0001), higher Rsyn (P < 0.0001), and longer t(1/2) (P = 0.008). Females have significantly greater baseline endogenous leptin levels and Rsyn than males (P < 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.
Wong
Shekman L
SL
Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California 91320, USA.
DePaoli
Alex M
AM
Lee
Jennifer H
JH
Mantzoros
Christos S
CS
D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000367:Age Factors; D004435:Eating / Q000502:physiology*; D005260:Female; D006801:Humans; D007700:Kinetics; D020738:Leptin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D012737:Sex Factors
D020738:Leptin; C122136:recombinant methionyl human leptin