PLASMA-PROTEIN BINDING-KINETICS OF VALPROIC ACID OVER A BROAD DOSAGE RANGE - THERAPEUTIC IMPLICATIONS

The aim of the study was to characterize, from the relationship betwee n total and free serum levels of valproic acid obtained over a broad d osage range (10-50 mg/kg), the parameters defining the in-vivo kinetic behaviour of the binding of valproic acid to plasma proteins, their p harmacokinetic and clinical repercussions, and their application to th erapeutic drug monitoring (TDM). The study was performed in nine healt hy adults (20-35 years) who were given doses of 1000 (group A), 2000 ( group B) and 3000 mg (group C) of sodium valproate according to a comp ensated cross-over design, simultaneously determining the total and fr ee serum levels of valproic acid over a 24-h period. The mean free fra ction increases with dose, although this increase is only significant (P < 0.05) for the highest dose (3000 mg). The variation in the free f raction of valproic acid begins to become significant (P<0.05) at a to tal drug concentration above 100 mg/l. The mean values of the dissocia tion constant (K) and binding sites (n) were 460 mumol/l and 1.79, res pectively, showing a variability of 86.6 and 38.7%, respectively, and a residual variability of 13.0%. Significant differences (P< 0.05) wer e found for the total plasma clearance (Cl) but not for the intrinsic plasma clearance (Cl(u)) values, despite their tendency to decrease wi th the dose. If TDM is to be used for valproic acid, it is the free se rum levels that should be determined, especially if high doses are adm inistered, because the total serum levels are not a true reflection of the free ones, as is the case of other anti-epileptic drugs.