Increased apparent oral clearance of valproic acid during intake of combined contraceptive steroids in women with epilepsy

Purpose: To determine potential changes in total and unbound serum valproic acid (VPA) concentrations at steady-state during a cycle of intake of combined hormonal contraceptive (HC) steroids. Methods: Blood samples were collected from nine women stabilized on VPA monotherapy on two separate randomized occasions: (i) at the end of the 4- to 7-day HC-free interval, and (ii) on the last day of the HC intake period. Trough concentrations of VPA in serum and serum ultrafiltrates were determined by fluorescence polarization immunoassay. Results: In all women, total and unbound VPA concentrations were higher during the HC-free interval than during HC intake (means ± SD: 425 ± 184 vs. 350 ± 145 μmol/L, respectively, for total VPA, p = 0.002, and 55 ± 37 vs. 39 ± 25 μmol/L, respectively, for unbound VPA, p = 0.005). Compared with the HC-free interval, HC intake was associated with a mean 21.5% increase in VPA total apparent oral clearance (from 8.0 ± 5.2 to 9.7 ± 6.4 ml/h/kg, p = 0.01) and a 45.2 % increase in VPA unbound apparent oral clearance (from 79 ± 81 to 115 ± 121 ml/h/kg, p = 0.029). Conclusions: The apparent oral clearance of total and unbound VPA increases during the HC intake period compared with the HC-free interval, probably due to induction of glucuronosyltransferase by ethinylestradiol. The magnitude of the change varies across individuals, being potentially clinically relevant in some cases. Serum VPA concentrations should be monitored when adding or discontinuing HC steroids, and possibly during the on-off intervals of a HC cycle.