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Possible mechanisms of low levels of plasma valproate concentration following simultaneous administration of sodium valproate and meropenem

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Drug interaction between meropenem (MEPM), a carbapenem of antibiotic agent, and sodium valproate (VPA), an anticonvulsant, was studied in rats and human volunteers. When sodium VPA and MEPM were administered simultaneously, the plasma VPA level was significantly lower and the blood cell/plasma VPA concentration ratio was significantly higher than after the administration of sodium VPA alone (control). Following the simultaneous administration of sodium VPA and MEPM, the pharmacokinetic parameters such as plasma VPA, volume of distribution (Vd) and clearance (CL) were significantly increased, while the maximum plasma concentration (Cmax) and area under the plasma concentration- time curve (AUC) till 3 h were significantly decreased. The ratio of free (unbound) VPA to protein-bound VPA was significantly increased after the administration of MEPM. The concentration of VPA in brain tissue was significantly decreased after the simultaneous administration of VPA and MEPM. Competition between VPA and MEPM for a protein binding site resulted in increased plasma levels of free (unbound) VPA, which then distributed to various tissues, in particular, the blood cells, liver and kidney. VPA which distributed to the liver was metabolized there and excreted. Subsequently, the levels of VPA in the plasma and brain would be significantly decreased.


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