LEPTIN - ITS PHARMACOKINETICS AND TISSUE DISTRIBUTION

OBJECTIVE: The pharmacokinetics and tissue distribution of leptin in r ats was investigated. DESIGN: A catheter was inserted in the right jug ular vein of rats on the day prior to experiment. The next day, blood was sampled and then a tracer dose of radioiodinated hormone was admin istered via the catheter. Thereafter, small (200 mu l) samples of bloo d 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 calc ulated after fitting a bi-exponential equation describing a two-pool m odel of plasma leptin distribution. Selected time-point plasma samples were fractioned using size exclusion chromatography and the leptin di stribution determined. RESULTS: The two pool model described the pharm acokinetics of leptin in two forms: an initial fast decaying pool (t(1 /2) = 3.4 min) and a slower decaying pool (t(1/2) = 71 min) with an ov erall clearance rate of 6.16 ml/min/kg. Size exclusion chromatography showed a persistent peak (all time-points tested) of I-125-leptin corr esponding to the plasma albumin peak. The size of the free I-125-lepti n peak became diminished or absent in later time-point plasma samples. Tissue distribution of leptin at 60 min and 180 min time-points showe d that the small intestine contained the highest concentration of lept in, almost four times the level found in kidneys, liver, stomach and l ungs. I-125-leptin was least abundant in skin, muscle, heart, caecum a nd brain. CONCLUSION: The pharmacokinetics of leptin are affected by t hree important factors: 1) its ability to bind to a plasma carrier mol ecule which increases its half-life; 2) its association with abundant peripheral tissue binding sites which creates an additional pool of le ptin and 3) the rate of synthesis of leptin which may be less importan t than originally believed as the prolonged half-life and the addition al pool of tissue binding sites are important factors in determining i ts plasma concentration.