Hill R A, Margetic S, Pegg G G, Gazzola C
Queensland Beef Industry Institute, Department of Primary Industries, Rockhampton, Australia.
Int J Obes Relat Metab Disord. 1998 Aug;22(8):765-70. doi: 10.1038/sj.ijo.0800656.
The pharmacokinetics and tissue distribution of leptin in rats was investigated.
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 microl) 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 fitting 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.
The two pool model described the pharmacokinetics 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 overall clearance rate of 6.16 ml/min/kg. Size exclusion chromatography showed a persistent peak (all time-points tested) of 125I-leptin corresponding to the plasma albumin peak. The size of the free 125I-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. 125I-leptin was least abundant in skin, muscle, heart, caecum and brain.
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.
研究瘦素在大鼠体内的药代动力学及组织分布情况。
实验前一天在大鼠右颈静脉插入导管。次日，采集血液样本，然后通过导管给予微量放射性碘标记的激素。此后，每隔一定时间采集少量（200微升）血液样本。在不同采样时间进行了两项实验。对血浆和组织样本中的三氯乙酸沉淀放射性进行计数。拟合描述血浆瘦素分布双池模型的双指数方程后计算药代动力学参数。使用尺寸排阻色谱法对选定时间点的血浆样本进行分离，并确定瘦素分布情况。
双池模型以两种形式描述了瘦素的药代动力学：一个初始快速衰减池（t(1/2)=3.4分钟）和一个较慢衰减池（t(1/2)=71分钟），总清除率为6.16毫升/分钟/千克。尺寸排阻色谱显示，对应于血浆白蛋白峰，125I-瘦素存在一个持续峰（所有测试时间点）。在后期时间点的血浆样本中，游离125I-瘦素峰的大小变小或消失。在60分钟和180分钟时间点的瘦素组织分布显示，小肠中瘦素浓度最高，几乎是肾脏、肝脏、胃和肺中浓度的四倍。125I-瘦素在皮肤、肌肉、心脏、盲肠和大脑中含量最少。
瘦素的药代动力学受三个重要因素影响：1）其与血浆载体分子结合的能力，这增加了其半衰期；2）其与丰富的外周组织结合位点的关联，这形成了额外的瘦素池；3）瘦素的合成速率，其重要性可能不如最初认为的那样，因为延长的半衰期和额外的组织结合位点池是决定其血浆浓度的重要因素。
