Premium
Plasma protein binding kinetics of valproic acid over a broad dosage range: therapeutic implications
Author(s) -
Bellver M. J. Gómez,
Sánchez M. J. Garcéa,
Gonzalez A. C. Alonso,
Buelga D. Santos,
Dominguez–Gil A.
Publication year - 1993
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/j.1365-2710.1993.tb00612.x
Subject(s) - valproic acid , free fraction , pharmacokinetics , chemistry , pharmacology , sodium , in vivo , drug , medicine , epilepsy , microbiology and biotechnology , organic chemistry , psychiatry , biology
SUMMARY The aim of the study was to characterize, from the relationship between total and free serum levels of valproic acid obtained over a broad dosage range (10–50 mg/kg), the parameters defining the in–vivo kinetic behaviour of the binding of valproic acid to plasma proteins, their pharmacokinetic and clinical repercussions, and their application to therapeutic drug monitoring (TDM). The study was performed in nine healthy 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 compensated cross–over design, simultaneously determining the total and free serum levels of valproic add over a 24–h period. The mean free fraction increases with dose, although this increase is only significant (P <0 05) for the highest dose (3000 mg). The variation in the free fraction of valproic acid begins to become significant (P < 0>05) at a total drug concentration above 100 mg/1. The mean values of the dissociation constant (K) and binding sites (n) were 460 μmol/l and 179, respectively, showing a variability of 866 and 387%, respectively, and a residual variability of 130%. Significant differences (P < 005) were found for the total plasma clearance (Cl) but not for the intrinsic plasma clearance (CI u ) values, despite their tendency to decrease with the dose. If TDM is to be used for valproic acid, it is the free serum levels that should be determined, especially if high doses are administered, because the total serum levels are not a true reflection of the free ones, as is the case of other anti–epileptic drugs.