Safety Profile, Toxicokinetic, and Intestinal Absorption Differences of a Naturally-Derived Anti-Rheumatic Drug,...

Background/Objective: Sinomenine hydrochloride (SH), a natural anti-rheumatic drug derived from the Chinese medicinal plant Sinomenium acutum, demonstrates disease-modifying properties but lacks comprehensive safety and toxicokinetic (TK) comparisons between physiological and pathological states. This study evaluated SH's safety profile, TK parameters, and intestinal absorption differences in adjuvant-induced arthritis (AIA) and normal rats. Methods: Safety assessments determined median lethal doses (LD₅₀) in female Sprague Dawley rats. TK parameters were analyzed via a validated ultrahigh performance liquid chromatography-tandem mass spectrometry approach after single oral administration of 600 mg/kg SH. Plasma protein binding (PPB) were measured using equilibrium dialysis. Intestinal absorption was evaluated through everted gut sac experiments, with P-glycoprotein (P-gp) inhibition tested via verapamil co-administration. Results: LD₅₀ values revealed AIA rats tolerated SH better than normal rats (1179 vs. 805 mg/kg). TK analysis showed that C_max, AUC_(0-t), and AUC_(0-∞) of SIN in normal rats were 2.01, 1.94, and 2.14 times higher than in AIA rats, respectively, while CL/F and V/F in AIA rats were 2.24 times greater. In addition, the PPB of SIN in normal rats was 2 times greater than that in AIA rats. AIA rats exhibited significantly lower SH absorption in the jejunum and ileum compared to normal rats. Notably, verapamil co-administration markedly increased SH absorption across most intestinal segments. Conclusions: Pathological states significantly alter SH's safety and TK profiles. Enhanced tolerance in AIA rats correlates with reduced intestinal absorption via altered P-gp activity and decreased PPB. These findings emphasize the necessity of disease-specific evaluations for optimizing SH's therapeutic safety in pathological contexts.