Abstract
The interindividual relationship between unbound fraction of valproic acid and some factors such as total drug concentration, level of albumin, free fatty acids (FFA) and total bilirubin was investigated after repeated oral doses in 7 healthy adults. All serum samples (n=63) were collected just prior to the last dose and the following times there-after.
The correlation between unbound fraction and both corresponding each variable value and ratio of FFA/albumin and total bilirubin/albumin was determined in all samples (method (1)). Secondly, the correlation between individual average unbound fraction and both average values for each variable and ratio of FFA/albumin and total bilirubin/albumin of individual was also determined (method (2)).
For applied method (1), there was significant positive correlation between unbound fraction and both total drug concentration (P<0.001) and FFA/albumin ratio (P<0.01). On the other hand, for applied method (2), there was significant positive correlation only between average unbound fraction and average value for total drug concentration (P<0.001).
In the evaluation on these results by using in vivo binding parameters (K for association constant, and (P) for concentration of free protein) of the Scatchard plot, we observed the specific binding characteristics between valproic acid and serum albumin within the investigated range of total concentration (<420μmol/l). Additionally, we showed that the mechanism of altered binding characteristics depended onn both changes in K (P) affected by average total concentration and K by average FFA/albumin ratio.
