Browne T R, Szabo G K, Schumacher G E, Greenblatt D J, Evans J E, Evans B A
Department of Neurology and Pharmacology, Boston University School of Medicine, MA.
J Clin Pharmacol. 1992 Dec;32(12):1141-5.
The authors show that for a drug cleared by one enzyme the area under the serum concentration-time curve from time 0 to infinity (AUC0-INF) of a test dose can be expressed as AUC0-INF = TD x F x (Km + C)/Vmax where TD is test dose size, F is fraction absorbed, C is drug serum concentration at the time of the study, and Km and Vmax are the Michaelis constant and maximum velocity of the enzyme. This equation predicts the AUC0-INF produced by a given tracer dose of drug will vary directly with C in drugs with nonlinear pharmacokinetic properties (i.e., drugs whose value for C approaches or exceeds Km) if C is held constant by administration of tracer and maintenance doses of drug. The AUC0-INF produced by intravenous tracer doses of 150 mg of 13C15N2-sodium phenytoin was determined in 15 subjects at 30 different values of C. AUC0-INF showed a high degree of direct linear correlation with C (AUC0-INF (ug x hr/mL) = 35.4 + 8.1 x C (ug/mL), r = 0.885, P < .0001). Consequences of this observation for relative bioavailability studies of drugs with nonlinear pharmacokinetic properties are discussed.
作者表明，对于由一种酶清除的药物，试验剂量从时间0到无穷大的血清浓度 - 时间曲线下面积（AUC0 - INF）可表示为AUC0 - INF = TD×F×(Km + C)/Vmax，其中TD是试验剂量大小，F是吸收分数，C是研究时的药物血清浓度，Km和Vmax是该酶的米氏常数和最大速度。该方程预测，如果通过给予示踪剂和维持剂量的药物使C保持恒定，那么对于具有非线性药代动力学特性的药物（即C值接近或超过Km的药物），给定示踪剂剂量的药物产生的AUC0 - INF将与C直接成比例变化。在15名受试者中，在30个不同的C值下测定了静脉注射150 mg 13C15N2 - 苯妥英钠示踪剂剂量产生的AUC0 - INF。AUC0 - INF与C呈现高度直接线性相关（AUC0 - INF(μg×hr/mL) = 35.4 + 8.1×C(μg/mL)，r = 0.885，P <.0001）。讨论了这一观察结果对具有非线性药代动力学特性药物的相对生物利用度研究的影响。
