A New Approach to Establishing Individualized Maintenance Doses of Phenytoin

Use of Three Probes to Assess the Influence of Sex on Hepatic Drug Metabolism

“…Thus, our single-sam ple estimates of PHT kinetic parameters (Vmax/Km) based on salivary PHT concentra tions are in line with Vmax/Km values refer enced to unbound PHT which have been estimated from steady-state PHT measure ments in plasma. We have reported this ob servation in considerably more detail else where [13].…”

“…When steady-state plasma con centrations of PHT were used as an index of sex-based differences in PHT metabolism, they were found to be 20% lower among women though this difference was not a sta tistically significant one [7], Direct compari sons of our estimates of PHT CLujn, with those of other investigators cannot be made. However, given that CLuinl is the ratio of Vmax/Km where Km is referenced to unbound drug [13], and allowing Km to be set at 0.57 mg/1 (population Km referenced to total PHT concentrations [17] multiplied by a nominal free fraction of 0.1) and Vmax at 0.247 mg/kg/h [17], one can estimate a CLuin[ of 433 ml/h/kg to which our value (all subjects) of 483 (± 178) compares favora bly. Likewise, estimating CLU jnl from the data of Ludden et al [18] by referencing Km to unbound PHT, assuming a nominal free fraction of 0.1, and omitting the data of their patient J (CLuint s 2,720 ml/h/kg), a mean value of 473 mi/kg/h is obtained which ap proximates our value.…”

“…For example, the clearance estimates are assumed to re flect host factor influences on probe metabo lism. Since the estimates are relatively ro bust to errant assumptions about V [11,13], this is likely a reasonable assumption though not an infallible one. Moreover, real changes in bioavailability due to host factors would most likely be ascribed to changes in metab olism when using the single-sample proce dure with orally aministered probes.…”

“…V is the noncompartmenlal volume of distribution (l/kg) set at a previously determined sample mean value, and C, is the probe concentration measured at time (t). For PHT, concentrations were measured in salivary ultrafiltrates, and clearance estimates were adjusted by a divisor, g (0.7), to give estimates of intrinsic unbound clearance CLmm [13], V was fixed at 14 liters/kg.…”