Effects of Anticonvulsants on Plasma Levels and Entero-Hepatic Circulation of Valproic Acid and on Hepatic Drug Metabolizing Enzyme Acitivities in Rats

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To clarify the interaction between valproic acid (VPA) and anticonvulsive drugs such as phenytoin (DPH), phenobarbital (PB) and carbamazepine (CBZ), the effects of these anticonvulsants on the plasma levels and enterohepatic circulation of VPA and on drug metabolizing enzyme activities in liver in relation to their inductive effects were investigated in rats. After intravenous (i. v.) or oral administration, plasma VPA rapidly decreased, and this was followed by a secondary increase in plasma level of VPA due to enterohepatic circulation. When the drug was repeatedly coadministered with DPH or CBZ, the initial VPA elimination from plasma up to 1 h after dosing was less than with VPA alone, while PB significantly enhanced the disappearance of VPA. Judging from the decrease in the area under plasma VPA concentration-time curve from 2 to 9 h (AUC_<2-9>), the enterohepatic circulation of VPA was also decreased by PB, but not by DPH and CBZ. The in vitro and in vivo protein binding of VPA was almost unchanged in the presence of DPH. Cytochrome P-450 content and glucuronyltransferase activity were enhanced following repeated coadministration with PB, DPH or CBZ. These enzyme activities in the animals treated with VPA alone at various dosage levels, however, remained unchanged, indicating that VPA did not inhibit the hepatic drug metabolizing enzyme activities in rats.
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