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Pharmacokinetics of human leptin in mice and rhesus monkeys

International Journal of Obesity volume 24, pages 1579–1585 (2000)Cite this article

Abstract

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.

DESIGN: 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 μg/g). Blood samples were collected for leptin measurement at specific time points after leptin administration.

MEASUREMENTS: 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.

CONCLUSION: 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.

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Acknowledgements

The authors are grateful to Dr Landt for sharing his data, to Lilian Bengtsson and Lena Kvist for expert technical assistance and to Amgen Inc., Thousand Oaks, CA, for providing the recombinant leptin for the experiments. The work was supported by grants from the Swedish Medical Research Council (grant no 14X-6834), Albert Påhlsson and Novo Nordic Foundations, Swedish Diabetes Association, Malmö University Hospital and the Faculty of Medicine, Lund University (BA), and NIH grants DK-50129 and DK-5747 and the American Diabetes Association (PJH). We would also like to thank Jenny Short, Sarah Davis, and Vanessa Bakula for their help in coordinating and conducting the primate studies and Dr Andrew G Hendrickx and the Venture Research Program (NIH RR-00169) of the California Regional Primate Research Center for supporting this project.

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Authors and Affiliations

  1. Department of Medicine, Lund University, Malmö, Sweden

    B Ahrén

  2. Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA

    RM Baldwin

  3. Department of Nutrition, University of California, Davis, CA, USA

    PJ Havel

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Correspondence to B Ahrén.

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Ahrén, B., Baldwin, R. & Havel, P. Pharmacokinetics of human leptin in mice and rhesus monkeys. Int J Obes 24, 1579–1585 (2000). https://doi.org/10.1038/sj.ijo.0801447

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