Valproic acid dosage and plasma protein binding and clearance

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Abstract
Valproic acid [antiepileptic] clearance was determined in 6 normal subjects during a single-dose (250 mg) study and multiple-dose experiments of 500, 1000 and 1500 mg/day. Consecutive oral doses (8) were taken at 12-h 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/h per kg between the single-dose and the 500 mg/day steps (P = 0.05). Clearance was unchanged between the 500 and 1000 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 .+-. 71.0 to 72.0 .+-. 20.8 ml/h per kg (P = 0.025). In 4 subjects completing the 1500 mg/day step, clearance increased from 6.76 .+-. 1.48 ml/h per kg (1000 mg/day) to 8.20 .+-. 1.62 ml/h per kg, corresponding to a further increase in free fraction. Free fraction varied within a single dosing interval (%SD = 11-49%). The apparent dose-related decline in intrinsic clearance suggests autoinhibition or saturation of metabolism.