Mahmood I
Office of Clinical Pharmacology and Biopharmaceutics, Divison of Pharmaceutical Evaluation I, Food & Drug Administration, Rockville, MD 20852, USA.
J Pharm Pharmacol. 1999 Aug;51(8):905-10. doi: 10.1211/0022357991773320.
Pharmacokinetic parameters (clearance, CL, volume of distribution in the central compartment, VdC, and elimination half-life, t1/2beta) predicted by an empirical allometric approach have been compared with parameters predicted from plasma concentrations calculated by use of the pharmacokinetic constants A, B, alpha and beta, where A and B are the intercepts on the Y axis of the plot of plasma concentration against time and alpha and beta are the rate constants, both pairs of constants being for the distribution and elimination phases, respectively. The pharmacokinetic parameters of cefpiramide, actisomide, troglitazone, procaterol, moxalactam and ciprofloxacin were scaled from animal data obtained from the literature. Three methods were used to generate plots for the prediction of clearance in man: dependence of clearance on body weight (simple allometric equation); dependence of the product of clearance and maximum life-span potential (MLP) on body weight; and dependence of the product of clearance and brain weight on body weight. Plasma concentrations of the drugs were predicted in man by use of A, B, alpha and beta obtained from animal data. The predicted plasma concentrations were then used to calculate CL, VdC and t1/2beta. The pharmacokinetic parameters predicted by use of both approaches were compared with measured values. The results indicate that simple allometry did not predict clearance satisfactorily for actisomide, troglitazone, procaterol and ciprofloxacin. Use of MLP or the product of clearance and brain weight improved the prediction of clearance for these four drugs. Except for troglitazone, VdC and t1/2beta predicted for man by use of the allometric approach were comparable with measured values for the drugs studied. CL, VdC and t1/2beta predicted by use of pharmacokinetic constants were comparable with values predicted by simple allometry. Thus, if simple allometry failed to predict clearance of a drug, so did the pharmacokinetic constant approach (except for actisomide). The results of this study indicate that caution should be employed in interpreting plasma concentrations predicted for a drug in man by use of pharmacokinetic constants obtained in animals.
通过经验性异速生长方法预测的药代动力学参数（清除率CL、中央室分布容积VdC和消除半衰期t1/2β），已与根据药代动力学常数A、B、α和β计算血浆浓度所预测的参数进行了比较，其中A和B分别是血浆浓度-时间曲线Y轴上的截距，α和β是速率常数，这两对常数分别用于分布相和消除相。头孢匹胺、阿替索米德、曲格列酮、丙卡特罗、拉氧头孢和环丙沙星的药代动力学参数是根据从文献中获得的动物数据进行换算的。使用了三种方法来生成预测人体清除率的曲线：清除率对体重的依赖性（简单异速生长方程）；清除率与最大寿命潜能（MLP）的乘积对体重的依赖性；清除率与脑重的乘积对体重的依赖性。通过使用从动物数据获得的A、B、α和β来预测人体中的药物血浆浓度。然后使用预测的血浆浓度来计算CL、VdC和t1/2β。将两种方法预测的药代动力学参数与测量值进行了比较。结果表明，简单异速生长法对阿替索米德、曲格列酮、丙卡特罗和环丙沙星的清除率预测效果不佳。使用MLP或清除率与脑重的乘积可改善这四种药物清除率的预测。除曲格列酮外，通过异速生长法预测的人体VdC和t1/β与所研究药物的测量值具有可比性。使用药代动力学常数预测的CL、VdC和t1/β与简单异速生长法预测的值具有可比性。因此，如果简单异速生长法无法预测药物的清除率，药代动力学常数法也同样无法预测（阿替索米德除外）。本研究结果表明，在解释使用从动物获得的药代动力学常数预测的人体药物血浆浓度时应谨慎。
