Studies with stable isotopes III: Pharmacokinetics of tracer doses of drug

Stable isotope labeled tracer doses of phenytoin (PHT) and phenobarbital (PB) were given intravenously before and four and 12 weeks after beginning monotherapy in two groups of six patients. Phenytoin demonstrated nonlinear pharmacokinetics, while PB demonstrated linear pharmacokinetics. Each of the 36 sets of tracer dose serum concentration versus time data points appeared linear during the elimination phase on semilog plots, and each demonstrated a high degree of linearity using semilog regression analysis (r2 = .977-.999, P less than .001, for PHT; r2 = .791-.996, P less than .005, for PB). We conclude tracer doses administered at steady-state serum concentration will exhibit linear serum concentration versus time relationships on semilog plots regardless of whether the steady-state serum concentration is in the linear or the nonlinear portion of a drug's dose versus steady-state serum concentration relationship. The mechanism and implications of this conclusion are discussed.