TY - JOUR
T1 - Increased apparent oral clearance of valproic acid during intake of combined contraceptive steroids in women with epilepsy
AU - Galimberti, Carlo Andrea
AU - Mazzucchelli, Iolanda
AU - Arbasino, Carla
AU - Canevini, Maria Paola
AU - Fattore, Cinzia
AU - Perucca, Emilio
PY - 2006/9
Y1 - 2006/9
N2 - 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.
AB - 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.
KW - Contraceptive steroids
KW - Drug interaction
KW - Epilepsy
KW - Pharmacokinetics
KW - Valproic acid
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U2 - 10.1111/j.1528-1167.2006.00629.x
DO - 10.1111/j.1528-1167.2006.00629.x
M3 - Article
C2 - 16981874
AN - SCOPUS:33748708898
VL - 47
SP - 1569
EP - 1572
JO - Epilepsia
JF - Epilepsia
SN - 0013-9580
IS - 9
ER -