Leptin: its pharmacokinetics and tissue distribution

Abstract

OBJECTIVE: The pharmacokinetics and tissue distribution of leptin in rats was investigated. DESIGN: A catheter was inserted in the right jugular vein of rats on the day prior to experiment. The next day, blood was sampled and then a tracer dose of radioiodinated hormone was administered via the catheter. Thereafter, small (200 m ml) samples of blood were taken at regular intervals. Two experiments were conducted over different sampling times. TCA precipitated radioactivity was counted in samples of plasma and tissues. Pharmacokinetic parameters were calculated after ®tting a bi-exponential equation describing a two-pool model of plasma leptin distribution. Selected time-point plasma samples were fractioned using size exclusion chromatography and the leptin distribution determined. RESULTS: The two pool model described the pharmacokinetics of leptin in two forms: an initial fast decaying pool (t 3.4 min) and a slower decaying pool (t1a 2 71 min) with an overall clearance rate of 6.16 mlaminakg. Size exclusion chromatography showed a persistent peak (all time-points tested) of 125 I-leptin corresponding to the plasma albumin peak. The size of the free 125 I-leptin peak became diminished or absent in later time-point plasma samples. Tissue distribution of leptin at 60 min and 180 min time-points showed that the small intestine contained the highest concentration of leptin, almost four times the level found in kidneys, liver, stomach and lungs. 125 I-leptin was least abundant in skin, muscle, heart, caecum and brain. CONCLUSION: The pharmacokinetics of leptin are affected by three important factors: 1) its ability to bind to a plasma carrier molecule which increases its half-life; 2) its association with abundant peripheral tissue binding sites which creates an additional pool of leptin and 3) the rate of synthesis of leptin which may be less important than originally believed as the prolonged half-life and the additional pool of tissue binding sites are important factors in determining its plasma concentration.

Pharmacokinetics of human leptin in mice and rhesus monkeys

“…30 When these data were reanalyzed and modeled using the same approach employed in the current study, the calculated half-lives and mean residence times, although slightly less, were comparable to our results (Landt unpublished results). Similar values were obtained by Hill et al using a dose that was approximately 1a1000 of those used in the current study and in the study by Cumin et al 31 The shorter calculated half-lives observed in these studies may simply be attributable Table 2 Pharmacokinetic characteristics of recombinant met-human leptin when administered intraperitoneally (10 mgag body weight) to C57BLa6J mice fed a normal diet (n 6) or a high-fat diet (n 8) Leptin pharmacokinetics B Ahre Ân et al to a shorter sampling period, and hence the terminal elimination phase was de®ned by a minimal number of later time points. It is clear from comparing several different studies, using doses ranging over at least three orders of magnitude, that the rates of elimination and mean residence times are similar across species.…”

Leptin

“…The bound fraction of leptin can be as high as 80% in humans with a leptin receptor mutation due to binding of leptin to circulating leptin receptors (96). An additional pool of leptin is bound to tissue-binding sites and is likely to contribute to the maintenance of steady-state plasma leptin levels (99). Based on anatomic and functional data, it appears that leptin exerts its effects on energy balance mainly by acting in the brain.…”

Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists

“…The Fc-hLeptin fusion and PEGylated hLeptin were shown to have half-lives of 10 h in mice and 48 h in rat, respectively (41)(42)(43). Compared with the hGH-CDR3H-coil-Herceptin fusion, hLeptin-CDR3H-coil-Herceptin displays a reduced half-life, which is attributable in part to the different species used in the two PK studies, and may also be due to proteolytic degradation of the fusion protein in vivo (44).…”