Valproic acid dosage and plasma protein binding and clearance.


Valproic acid clearance was determined in six normal subjects during a single-dose (250-mg) study and multiple-dose experiments of 500, 1,000, and 1,500 mg/day. Eight consecutive oral doses were taken at 12-hr intervals at each dosing level. Valproate levels and protein binding were determined at steady state. Clearance declined 20% from 8.33 +/- 2.44 to 6.67 +/- 1.25 ml/hr/kd between the single-dose and the 500-mg/day steps (p = 0.05). Clearance was unchanged between the 500- and 1,000-mg/day steps despite a 44% increase in mean free fraction (0.0703 +/- 0.0381 vs 0.1011 +/- 0.0438, p < 0.05), implying a balanced opposing decline in intrinsic clearance (from 89.2 +/0 71.0 to 72.0 +/- 20.8 ml/hr/kg; p = 0.025). In four subjects completing the 1,500-mg/day step, clearance increased from 6.76 +/- 1.48 ml/hr/kg (1,000- mg/day) to 8.20 +/- 1.62 ml/hr/kg, corresponding to a further increase in free fraction. Free fraction varied within a single dosing interval (%SD = 11% to 49%). The apparent dose-related decline in intrinsic clearance suggests autoinhibition or saturation of metabolism.


Citations per Year

680 Citations

Semantic Scholar estimates that this publication has 680 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Bowdle1980ValproicAD, title={Valproic acid dosage and plasma protein binding and clearance.}, author={Andrew Bowdle and Indravadan H. Patel and Ren{\'e} H. Levy and Alan J Wilensky}, journal={Clinical pharmacology and therapeutics}, year={1980}, volume={28 4}, pages={486-92} }