Studies With Stable Isotopes I: Changes in Phenytoin Pharmacokinetics and Biotransformation During Monotherapy

Abstract

Six patients were given tracer doses of ¹³C¹⁵N₂‐phenytoin (PHT) before and four and 12 weeks after beginning monotherapy. The following significant (P < .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 vaiues as the serum concentration rises to steady state. Stable iostope methods are particularly suitable for investigating such phenomena.