Pharmacokinetic-Pharmacodynamic Modeling of the Immune-Enhancing Effect of Shikimic Acid in Growing Pigs.

Abstract

Shikimic acid (SA), extracted from the fruit of shikimi-no-ki, is used both as a preservative in the food industry and as an intermediate for a variety of active ingredients with a wide range of pharmacological functions. A deeper understanding of the pharmacokinetic process of SA in pigs and its impact on humoral immunity could prove invaluable in facilitating its clinical application in veterinary and human medicine. The pharmacokinetic study employed a two-period, two-sequence, crossover design to animal experiments and developed a novel method of pig plasma preparation using water as an extractant and ionization promoter, followed by purification and enrichment on a MAX solid phase extraction (SPE) column. The results showed that SA is rapidly absorbed after intragastric administration (50 mg/kg BW), reaching a plasma C_max of 10,823.44 ng/mL at 1.78 h, followed by rapid elimination, with a t_1/2 of 1.81 h, consistent with a one-compartment model. The results for intravenous administration (2 mg/kg BW) were consistent with a two-compartment open model with a t_1/2 of 3.66 h, with concentrations below the limit of quantification (LOQ) observed beyond 12 h postdose. The absolute bioavailability of SA in pigs was calculated to be 21.68%. Furthermore, the Pearson's correlation analysis demonstrated a strong positive correlation between SA concentration in pig plasma and the changes of C3, C4 and IgG, IgA, and IgM (0.6 < R < 1, P < 0.0001). A more detailed pharmacokinetic-pharmacodynamic (PK-PD) modeling analysis of the intravenous group revealed the EC₅₀/C_max values of approximately 10%, with all γ values exceeding 3. This study was the inaugural investigation into the pharmacokinetics of SA in growing pigs, and it also revealed that SA has the potential to act as an immunopotentiator.