Abstract
A clinical pharmacological study was conduct ed to disclose a pertinent correlation between oral dosage of valproate sodium (VPA) and the serum concentration of dipropyl acetate in steady state determined by gasliguid chromatography.The following two conditions were deliberately distinguished;firstly, the comparison of the dose-level correlations in reference to the age of the patients especially of children, and secondly, the distinction between the patients receiving VPA along with other antiepileptic drugs (poly pharmacy) and those taking VPA as the sole drug (monopharmacy).
One hundred and twenty-five assays from 116 patients in monopharmacy and 92 assays from 91 patients in polypharmacy were studied.All thepatients were“compliant”and their blood speci-mens were taken 2 to 3 hours after the first mor-ning dose.
Almost linear relationship was demonstrated between the dosage and the concentration.The level-dose ratios were apparently high in adult patients over 15 years of age, compared to those of younger children under 6 years.Regardless of the age of the patients, dipropyl acetate concen-trations attained significantly to a higher level in monpharmacy than those on polypharmacy, that is, 111.3±18.0μg/ml and 86.5+14.9μg/ml re spectively (40 assays each), when adult patients were receiving a comparable dose of VPA at 15±2.5 mg/kg/day.
In an attempt to elucidate possible interaction effects of phenytoin (PHT) exerting on dipropyl acetate concentration, a prospective study was carried out.To eliminate the influnce of daily fluctuation of dipropyl acetate concentration, blood specimens were taken immediately before the first morning dose in this study.In 3 patients, after VPA levels reached a certain steady state (12.3 to 16.5 mg/kg/day), PHT (3.8 to 4.6mg/kg/day) was added.In each case, as the PHT concentration increased toward the steady state, the dipropyl acetate concentration decreased inver sely with the rate of 30 to 45%.
In another timecourse study done on a healthy volunteer, the decreasing effect by PHT upon dipropyl acetate concentration (one-ffect) was exemplified by the fact that the dipropyl acetate concentration increaded again when concomitat ly used PHT was withdrawn (off-effect).
Since the accuracy of the measurements shown by coefficients of variation using spiked sera were as low as 2.3 to 3.3%, the result on both these on-and-off effects was convinced to be highly dependable.
As far as dipropyl acetate serum concentra tions are concerned, the following three condi tions have to be taken into consideration: 1. sampling time of blood specimens, 2.age of the patients especially of children, 3.presence of other concomitant antiepileptic drug (s), at least of PHT.
All these results suppors a view that VPA monopharmacy appeared to be rather rational so far as VPA was chosen as a primarily adequate antiepileptic drug.
