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Valproic acid dosage and plasma protein binding and clearance
Author(s) -
Bowdle T Andrew,
Patel Indravadan H,
Levy René H,
Wilensky Alan J
Publication year - 1980
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1980.192
Subject(s) - free fraction , valproic acid , pharmacokinetics , dosing , chemistry , metabolic clearance rate , metabolism , pharmacology , plasma concentration , clearance rate , dose–response relationship , plasma clearance , endocrinology , medicine , epilepsy , psychiatry
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/kg 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 ± 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. Clinical Pharmacology and Therapeutics (1980) 28, 486–492; doi: 10.1038/clpt.1980.192