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 <.0001). Consequences of this observation for relative bioavailability studies of drugs with nonlinear pharmacokinetic properties are discussed.