Pharmacokinetics of human leptin in mice and rhesus monkeys.
OBJECTIVE
The pharmacokinetic characteristics of human leptin were examined in rhesus monkeys and in C57BL/6J mice fed a normal chow or a high-fat diet.


METHODS
For the monkey study, in nine rhesus monkeys (body weight 12.4 +/- 2.4 kg; mean +/- s.d.), recombinant met-human leptin was injected intravenously or subcutaneously (1 mg/kg). For the mouse study, after 6 months of feeding C57BL/6J mice a high-fat diet (body weight 32.9 +/- 3.6 g; n = 8) or a control diet (24.5 +/- 1.2 g; n = 6), recombinant met-human leptin was administered intraperitoneally (10 microg/g). Blood samples were collected for leptin measurement at specific time points after leptin administration.


METHODS
Plasma leptin concentrations were determined by radioimmunoassay and pharmacokinetic analysis was performed.


RESULTS
Disposition of human leptin in rhesus monkeys was biphasic following intravenous administration, with a terminal phase half-life of 96.4 +/- 16.5 min and clearance of 1.8 +/- 0.2 ml/min/kg. Subcutaneously administered leptin was absorbed slowly, perhaps by a zero-order process as leptin levels appeared to plateau and remained elevated throughout the 8 h sampling period. In C57BL/6J mice, the absorption and elimination of human leptin were both first-order following intraperitoneal administration. Pharmacokinetic parameters did not differ between normal-weight mice fed a chow diet and obese mice fed a high-fat diet. The elimination half-life was 47.0 +/- 26.4 min in mice fed a high-fat diet and 49.5 +/- 12.0 min in mice fed a control diet.


CONCLUSIONS
The kinetics of leptin in rhesus monkeys were biphasic and clearance was similar to values previously reported in humans. The estimated half-life was 96.4 min in rhesus monkeys and 49.5 min in normal weight mice. The was no difference in leptin kinetics between high-fat fed and control mice, suggesting that the increased baseline leptin levels in the obese mice are due to increased leptin production and secretion.
Ahrén
B
B
Department of Medicine, Lund University, Malmö, Sweden. Bo.Ahren@medforsk.mas.lu.se
Baldwin
R M
RM
Havel
P J
PJ
D000042:Absorption; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D006207:Half-Life; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007700:Kinetics; D020738:Leptin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013045:Species Specificity
D004041:Dietary Fats; D020738:Leptin; D011994:Recombinant Proteins