Stable-isotope methodology for the bioavailability study of phenytoin during multiple-dosing regimens.

With the highly sensitive and specific gas chromatography-mass spectrometry (GC-MS), plasma concentrations resulting from an intravenous administration of only a small amount of stable isotopically labeled phenytoin (DPH-d10) were determined to obtain information on the accurate clearance values under steady-state conditions attained with unlabeled phenytoin (DPH-d0). A time course of DPH-d10 concentrations was followed simultaneously with DPH-d0 during dosing intervals by GC-MS, with DPH-d5 as an internal standard. The present stable-isotope methodology offered advantages for the estimation of absolute bioavailability of the oral phenytoin dose in patients, while normal therapy was continued and not withdrawn.