Pharmacokinetic-pharmacodynamic integration of shikimic acid in broilers: An indirect effect modeling approach

Shikimic acid (SA), a natural polyhydroxy cyclic organic acid, possesses significant anti-inflammatory and antioxidant activities; however, its pharmacokinetic (PK) profile and pharmacodynamic (PD) relationship in poultry remain poorly characterized. This study aimed to elucidate the PK characteristics of SA in broilers and its PD regulatory patterns on serum antioxidant indices. Sixteen healthy 5-week-old broilers were randomly assigned to intravenous (IV) and oral (PO) groups (50 mg/kg BW). Plasma SA concentrations were dynamically monitored via HPLC-MS/MS, while serum malondialdehyde (MDA), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC) were quantified simultaneously. PK parameters were calculated using non-compartmental analysis (NCA), and PK-PD integration was performed using an indirect effect model. The results showed that after IV administration, SA was extensively distributed and rapidly eliminated, with an apparent volume of distribution (V_z) of 0.35 ± 0.08 L/kg and an elimination half-life (t_1/2) of 1.61 ± 0.54 h. PO administration demonstrated moderate absorption characteristics, with a T_max of 3.38 ± 0.74 h and a C_max of 32.68 ± 7.15 µg/mL. Notably, the absolute bioavailability (F) of SA reached 40.37 % ± 7.22 %, which appears higher than values previously reported in mammals. Although a single dose significantly improved the oxidative status, the peak effect lagged behind the peak plasma concentration, exhibiting a typical hysteresis loop. Indirect effect model fitting yielded a low equilibrium rate constant (k_e0), strongly suggesting that SA may exert its antioxidant effects via indirect mechanisms rather than acting primarily as a direct scavenger. In conclusion, SA exhibits favorable absorption characteristics and moderate oral bioavailability in broilers, with an antioxidant profile characterized by indirect regulation, likely involving the activation of endogenous signaling pathways for sustained protection. This study provides an important scientific basis for the precision dosing of SA in poultry and the development of plant-derived anti-stress additives.