Tang Huadong, Mayersohn Michael
Bioanalytical Department, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA.
J Clin Pharmacol. 2006 Apr;46(4):398-400. doi: 10.1177/0091270005285457.
The prediction of a human clearance (CL) value for UCN-01, an extreme example of vertical allometry (a large overprediction by allometric scaling), was examined using commonly used simple allometry and the "rule of exponents," as well as a newly proposed model, which quantitatively incorporates plasma protein-binding information from rats and humans. Simple allometry and the rule of exponents were shown to overpredict the human CL value of UCN-01 by about 5000- and 1750-fold, respectively. The new model incorporating the ratio of fraction unbound between rats and humans improved the prediction by about 20-fold compared to the rule of exponents. The model is expected to improve if a more accurate measurement of the unbound fraction in human plasma is obtained. The prediction of volume distribution for UCN-01 by allometric scaling was also shown to be dependent on the difference of fraction unbound between animal species and humans. In summary, plasma protein binding has been demonstrated to be an important measure for interspecies scaling of pharmacokinetics.
利用常用的简单异速生长法和“指数规则”，以及一种新提出的定量纳入大鼠和人类血浆蛋白结合信息的模型，对UCN - 01（垂直异速生长的一个极端例子，异速生长比例存在大量高估）的人体清除率（CL）值进行了预测。结果表明，简单异速生长法和指数规则分别将UCN - 01的人体CL值高估了约5000倍和1750倍。与指数规则相比，纳入大鼠和人类未结合分数比值的新模型将预测值提高了约20倍。如果能获得更准确的人体血浆未结合分数测量值，该模型的预测效果有望进一步改善。通过异速生长比例法对UCN - 01的分布容积进行预测，结果还表明其依赖于动物物种与人类之间未结合分数的差异。总之，血浆蛋白结合已被证明是药代动力学种间比例缩放的一项重要指标。
