Bioavailability Studies of Drugs with Nonlinear Pharmacokinetics: I. Tracer Dose AUC Varies Directly with Serum Concentration

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 he expressed as AUC0—INF = TD × F × (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 · hr/mL) = 35.4 + 8.1 × C (ug/mL), r = 0.885, P