Studies with stable isotopes I: Changes in phenytoin pharmacokinetics and biotransformation during monotherapy.

Six patients were given tracer doses of 13C15N2-phenytoin (PHT) before and four and 12 weeks after beginning monotherapy. The following significant (P less than .05) changes occurred during monotherapy: (1) Apparent (from tracer doses) PHT total clearance by linear method decreased; (2) apparent PHT elimination half-life increased; (3) apparent mean PHT serum concentration per unit dose increased; (4) apparent rate of excretion of p-hydroxyphenyl-phenylhydantoin (p-HPPH) decreased; (5) apparent rate of excretion of PHT dihydrodiol increased; and (6) apparent PHT total clearance and elimination half-life and apparent p-HPPH rate of excretion were dose dependent. Phenytoin apparent pharmacokinetic and biotransformation values undergo a typical series of changes after beginning monotherapy at typical dosing rates, because PHT's dose-dependent pharmacokinetics result in differing apparent values as the serum concentration rises to steady state. Stable isotope methods are particularly suitable for investigating such phenomena.