Pharmacokinetic study of valproic acid sustained-release preparation in patients undergoing brain surgery

Pharmacokinetics of valproic acid sustained-release preparation (VPA-SR) were studied in nine patients undergoing surgery for brain tumor. Total (t) and free (f) serum concentrations were analyzed in samples drawn during the day of brain surgery and compared with levels from a postoperative day. The area under the curve (AUCt) and clearance (CLt) of the total concentration did not differ on these occasions. In contrast, statistically significant differences were observed in AUCf and CLf between the two occasions; increased AUCf and decreased CLf were observed on the day of surgery. A significant relation was found between the average free fraction (AUCf/AUCt on operation day per AUCf/AUCt on postoperative day) and estimated blood loss during operation (r = 0.82; p < 0.001). In addition, a significant relation was found between simple free fraction and the intraoperative albumin level in serum (r = -0.68; p < 0.001). These findings indicate that the increased VPA free concentration is due to low serum albumin level secondary to blood loss and that there has been a decrease in intrinsic clearance during operation.