Liquid and semisolid enteral nutrition formulations alter the pharmacokinetics of orally administered valproate in rats.

BACKGROUND & AIMS: Valproate (VPA), an antiepileptic drug, requires therapeutic monitoring because alterations in gastrointestinal absorption may affect its therapeutic efficacy. Although enteral nutrition (EN) alters the pharmacokinetics of several antiepileptic drugs, the effects of semisolid EN formulations on VPA pharmacokinetics remain unclear. In this study, we aimed to determine the effects of liquid and semisolid EN formulations on VPA pharmacokinetics and to explore the possible mechanisms underlying these interactions. METHODS: Rats were orally co-administered VPA with liquid or semisolid EN formulations, or with individual EN components, and then plasma VPA concentrations were measured over time. Pharmacokinetic parameters, including the area under the plasma concentration-time curve from 0 to 2 h (AUC0→2h), maximum plasma concentration (Cmax), and time to maximum plasma concentration (Tmax), were evaluated to assess alterations in early VPA absorption. In addition, physicochemical properties, including viscosity, osmolality, and binding rate, were examined. RESULTS: Co-administration of VPA with all four liquid EN formulations significantly reduced Cmax and AUC0→2h compared with those in the control group, although the magnitude and temporal profiles of the reductions differed among the formulations. Renalen LP showed the greatest reduction in AUC0→2h, which was approximately 70% lower than that in the control group. All four semisolid EN formulations significantly reduced Cmax and AUC0→2h compared with those in the control group, whereas Tmax was not significantly affected. Among individual components, agar agar markedly reduced plasma VPA concentrations, Cmax, and AUC0→2h. In contrast, dextrin and the other tested components did not significantly alter the pharmacokinetic parameters. The results of physicochemical analyses indicated that gel-forming properties and other formulation-specific physicochemical characteristics may have contributed to the observed interactions. CONCLUSIONS: EN altered VPA pharmacokinetics in a formulation-dependent manner. Semisolid EN formulation and specific EN components, particularly agar agar, may alter the early pharmacokinetics of VPA.